HRP20030432A2 - Novel crystal and solvate forms of ondansetron hydrochloride and processes for their preparation - Google Patents
Novel crystal and solvate forms of ondansetron hydrochloride and processes for their preparation Download PDFInfo
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- HRP20030432A2 HRP20030432A2 HR20030432A HRP20030432A HRP20030432A2 HR P20030432 A2 HRP20030432 A2 HR P20030432A2 HR 20030432 A HR20030432 A HR 20030432A HR P20030432 A HRP20030432 A HR P20030432A HR P20030432 A2 HRP20030432 A2 HR P20030432A2
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- Croatia
- Prior art keywords
- ondansetron hydrochloride
- ondansetron
- hydrochloride form
- ethanol
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- MKBLHFILKIKSQM-UHFFFAOYSA-N 9-methyl-3-[(2-methyl-1h-imidazol-3-ium-3-yl)methyl]-2,3-dihydro-1h-carbazol-4-one;chloride Chemical compound Cl.CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 MKBLHFILKIKSQM-UHFFFAOYSA-N 0.000 title claims description 272
- 238000000034 method Methods 0.000 title claims description 93
- 229960000770 ondansetron hydrochloride Drugs 0.000 title claims description 74
- 238000002360 preparation method Methods 0.000 title claims description 45
- 230000008569 process Effects 0.000 title claims description 30
- 239000013078 crystal Substances 0.000 title claims description 28
- 239000012453 solvate Substances 0.000 title description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 182
- 229960005343 ondansetron Drugs 0.000 claims description 85
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 claims description 76
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 53
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- 239000000203 mixture Substances 0.000 claims description 46
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- 238000010992 reflux Methods 0.000 claims description 39
- 239000002585 base Substances 0.000 claims description 36
- 150000004683 dihydrates Chemical class 0.000 claims description 32
- 239000000843 powder Substances 0.000 claims description 32
- 239000002245 particle Substances 0.000 claims description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 150000004682 monohydrates Chemical class 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 19
- 239000000725 suspension Substances 0.000 claims description 17
- FELGMEQIXOGIFQ-UHFFFAOYSA-N Ondansetron Chemical compound CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 239000012458 free base Substances 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 13
- 239000007788 liquid Substances 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 150000004677 hydrates Chemical class 0.000 claims description 12
- 238000002441 X-ray diffraction Methods 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 238000009826 distribution Methods 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 9
- 238000004090 dissolution Methods 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 230000036571 hydration Effects 0.000 claims description 6
- 238000006703 hydration reaction Methods 0.000 claims description 6
- 206010047700 Vomiting Diseases 0.000 claims description 5
- 239000012298 atmosphere Substances 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 5
- 238000012545 processing Methods 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 206010028813 Nausea Diseases 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 230000018044 dehydration Effects 0.000 claims description 4
- 238000006297 dehydration reaction Methods 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- 239000000155 melt Substances 0.000 claims description 4
- 230000008693 nausea Effects 0.000 claims description 4
- 230000008673 vomiting Effects 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 3
- 230000008018 melting Effects 0.000 claims description 3
- 150000002576 ketones Chemical group 0.000 claims description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 3
- 238000002955 isolation Methods 0.000 claims 2
- OGHBATFHNDZKSO-UHFFFAOYSA-N propan-2-olate Chemical group CC(C)[O-] OGHBATFHNDZKSO-UHFFFAOYSA-N 0.000 claims 2
- 238000000926 separation method Methods 0.000 claims 2
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 claims 1
- 229940005991 chloric acid Drugs 0.000 claims 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims 1
- 238000009210 therapy by ultrasound Methods 0.000 claims 1
- 239000007787 solid Substances 0.000 description 49
- 239000000243 solution Substances 0.000 description 40
- 239000011541 reaction mixture Substances 0.000 description 31
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 19
- 239000002244 precipitate Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- 238000001816 cooling Methods 0.000 description 7
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 6
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 6
- 239000001110 calcium chloride Substances 0.000 description 6
- 235000011148 calcium chloride Nutrition 0.000 description 6
- 229910001628 calcium chloride Inorganic materials 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- 208000031649 Postoperative Nausea and Vomiting Diseases 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000002411 thermogravimetry Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 238000001159 Fisher's combined probability test Methods 0.000 description 3
- 206010066962 Procedural nausea Diseases 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 238000010951 particle size reduction Methods 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- 206010066963 Procedural vomiting Diseases 0.000 description 2
- WGPMOVAPQPJDDK-UHFFFAOYSA-M [Cl-].[Ca+] Chemical compound [Cl-].[Ca+] WGPMOVAPQPJDDK-UHFFFAOYSA-M 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- -1 compound compound Chemical class 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- NSNHWTBQMQIDCF-UHFFFAOYSA-N dihydrate;hydrochloride Chemical compound O.O.Cl NSNHWTBQMQIDCF-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 229940100688 oral solution Drugs 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- DSXKDTZEIWTHRO-UHFFFAOYSA-N 1,2,3,9-tetrahydrocarbazol-4-one Chemical group N1C2=CC=CC=C2C2=C1CCCC2=O DSXKDTZEIWTHRO-UHFFFAOYSA-N 0.000 description 1
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 1
- 229940113081 5 Hydroxytryptamine 3 receptor antagonist Drugs 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000011164 primary particle Substances 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- VRPMUIGQHGIAOY-UHFFFAOYSA-M trimethyl-[(9-methyl-4-oxo-2,3-dihydro-1h-carbazol-3-yl)methyl]azanium;iodide Chemical compound [I-].C12=CC=CC=C2N(C)C2=C1C(=O)C(C[N+](C)(C)C)CC2 VRPMUIGQHGIAOY-UHFFFAOYSA-M 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 229940072018 zofran Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Otolaryngology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Steroid Compounds (AREA)
Description
Reference srodnih prijava References of related applications
Ova prijava poziva se na privremenu prijavu serijskog broja 60/244,283, predano 30. 10.2000.; privremenu prijavu serijskog broja 60/253,819, predano 29. 11. 2000. i privremenu prijavu serijskog broja 60/265,539, predano 31. 1. 2001. This application refers to provisional application serial number 60/244,283, filed 10/30/2000; provisional application serial number 60/253,819, submitted on 29/11/2000 and provisional application serial number 60/265,539, submitted on 31/01/2001
Područje izuma Field of invention
Predmetni izum odnosi se na nove polimorfne forme i hidrate ondansetron hidroklorida te postupke za pripremu polimorfnih i hidratnih formi ondansetron hidroklorida. The present invention relates to new polymorphic forms and hydrates of ondansetron hydrochloride and processes for the preparation of polymorphic and hydrate forms of ondansetron hydrochloride.
Pozadina izuma Background of the invention
(±) 1,2,3,9-tetrahidro-9-metil-3-[2-metil-1H-imidazol-1-il) metil]-4h-karbazol-4-on koji ima molekulsku strukturu (±) 1,2,3,9-tetrahydro-9-methyl-3-[2-methyl-1H-imidazol-1-yl)methyl]-4h-carbazol-4-one having the molecular structure
[image] [image]
je selektivni antagonist 5-HT3 receptora.' Poznat je pod generičkim imenom ondansetron. Ondansetron smanjuje mučninu kod pacijenata pod kemoterapijom. Grunberg, S. M.; Hesketh,-P. J. "Control of Chemotherapy-Induced emesis" N. Engl. J. Med. 1993, 329, 1790 - 96. Ondansetron je indiciran za sprečavanje mučnine i povraćanja povezanih s nekim vrstama kemoterapije protiv karcinoma, radioterapijom i postoperativnom mučninom i/ili povraćanjem. is a selective 5-HT3 receptor antagonist.' It is known by the generic name ondansetron. Ondansetron reduces nausea in patients undergoing chemotherapy. Grunberg, S.M.; Hesketh,-P. J. "Control of Chemotherapy-Induced emesis" N. Engl. J. Med. 1993, 329, 1790 - 96. Ondansetron is indicated for the prevention of nausea and vomiting associated with some types of cancer chemotherapy, radiotherapy, and postoperative nausea and/or vomiting.
Hidrokloridna sol ondansetrona je općenito sigurna za oralno davanje pacijentu bez uzrokovanja iritacije ili drugih nepovoljnih efekata. Hidrokloridna sol prodaje se u obliku tableta i u obliku oralne otopine pod nazivom proizvoda Zofran. The hydrochloride salt of ondansetron is generally safe for oral administration to the patient without causing irritation or other adverse effects. The hydrochloride salt is sold in tablet form and as an oral solution under the product name Zofran.
Aktivni sastojak tablete je dihidrat ondansetron hidroklorida koji sadrži vezane dvije molekule vode u kristalnoj rešeci ondansetron hidroklorida. The active ingredient of the tablet is ondansetron hydrochloride dihydrate, which contains two water molecules bound in the crystal lattice of ondansetron hydrochloride.
Predmetni izum odnosi fizikalna svojstva čvrstog stanja ondansetron hidroklorida. Na ova svojstva može se utjecati kontroliranjem uvjeta pod kojima se hidrokloridna sol dobiva u čvrstom stanju. Fizikalna svojstva čvrstog stanja uključuju, na primjer, protočnost samljevene krutine. Protočnost utječe na lakoću postupanja s tvari za vrijeme obrade u farmaceutski proizvod. Kada čestice spoja u prahu ne protiču lagano jedna pokraj druge, specijalist za formuliranje mora tu činjenicu uzeti u obzir prilikom razvoja formulacije u obliku tablete ili kapsule, što zahtijeva korištenje sredstava za klizanje kao što je koloidni silicijev dioksid, talk, škrob ili trobazni kalcijev fosfat. The present invention relates to the physical properties of the solid state of ondansetron hydrochloride. These properties can be influenced by controlling the conditions under which the hydrochloride salt is obtained in the solid state. Physical properties of the solid state include, for example, the flowability of the ground solid. Flowability affects the ease of handling the substance during processing into a pharmaceutical product. When the powder compound particles do not flow easily past each other, the formulator must take this fact into account when developing a tablet or capsule formulation, which requires the use of glidants such as colloidal silica, talc, starch, or tribasic calcium phosphate .
Drugo važno svojstvo čvrstog stanja farmaceutskog spoja je njegova brzina otapanja u vodenoj tekućini. Brzina otapanja aktivnog sastojka u želučanoj tekućini pacijenta može imati terapeutske posljedice s obzirom da ona postavlja gornju granicu brzine kojom oralno primijenjen aktivni sastojak može doći u krvotok pacijenta. Brzina otapanja se također uzima u obzir pri formuliranju sirupa, napitaka i drugih tekućih medikamenata. Čvrsta forma spoja može također imati utjecaja na njegovo ponašanje prilikom komprimiranja i na stabilnost prilikom skladištenja. Another important property of the solid state of a pharmaceutical compound is its rate of dissolution in an aqueous liquid. The rate of dissolution of the active ingredient in the patient's gastric fluid can have therapeutic consequences since it sets the upper limit of the rate at which the orally administered active ingredient can reach the patient's bloodstream. Dissolution rate is also taken into account when formulating syrups, drinks and other liquid medications. The solid form of the compound can also have an effect on its behavior during compression and on its stability during storage.
Na ove važne fizikalne karakteristike utječe konformacija i orijentacija molekula u jediničnoj ćeliji koja definira određenu polimorfnu formu tvari. Llacer i suradnici su postavili pretpostavku da bi se različite spektroskopke karakteristike različito pripremljenih uzoraka ondansetron slobodne baze mogle pripisati dvjema različitim konfiguracijama oko metilenskog mosta između 1,2,3,9-tetrahidrokarbazol-4-on prstena i imidazolskog prstena. Llacer, J. M.; Gallardo, V.; Parera, A. Ruiz, M. A. Intern. J. Pharm., 177, 1999, 221-229. These important physical characteristics are influenced by the conformation and orientation of the molecules in the unit cell, which defines a certain polymorphic form of the substance. Llacer et al hypothesized that the different spectroscopic characteristics of differently prepared ondansetron free base samples could be attributed to two different configurations around the methylene bridge between the 1,2,3,9-tetrahydrocarbazol-4-one ring and the imidazole ring. Llacer, J.M.; Gallardo, V.; Parera, A. Ruiz, M.A. Intern. J. Pharm., 177, 1999, 221-229.
Kristalna polimorfna forma spoja može pokazivati termičko ponašanje različito od amorfne tvari ili druge polimorfne forme. Termičko ponašanje se mjeri u laboratoriju postupcima kao što je kapilarno određivanje točke taljenja, termogravimetrijska analiza (TGA) i diferencijalna skanirajuća kalorimetrija (DSC) te se može koristiti za razlikovanje nekih polimorfnih formi od drugih. Određena polimorfna forma može također dovesti do izraženih spektroskopskih svojstava koja se mogu otkriti rendgenskom kristalografijom praškastog uzorka, 13C NMR spektrometrijom čvrstog stanja i infracrvenom spektrometrijom. Postoji niz različitih postupaka koji imaju mogućnost za proizvodnju različitih kristalnih formi spoja. Primjeri uključuju kristalizaciju, probavljanje kristala, sublimaciju i termičku obradu. A crystalline polymorphic form of a compound may exhibit thermal behavior different from an amorphous substance or other polymorphic form. Thermal behavior is measured in the laboratory by methods such as capillary melting point determination, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphs from others. A particular polymorphic form can also lead to pronounced spectroscopic properties detectable by powder sample X-ray crystallography, solid state 13C NMR spectrometry, and infrared spectrometry. There are a number of different processes that have the ability to produce different crystalline forms of the compound. Examples include crystallization, crystal digestion, sublimation, and heat treatment.
U. S. Patent No. 4,695,578, primjer 1a, iznosi preparaciju ondansetrona alkiliranjem 2-metilimidazola pomoću 2,3,4,9-tetrahidro-N,N,N,9-tetrameti1-4-okso-1H-karbazol-3-metanaminium jodida. U ovom primjeru ondansetron je izoliran kao njegova hidrokloridna sol suspendiranjem reakcijskog produkta u smjesi apsolutnog etanola i etanolske otopine HCl, zagrijavanjem suspenzije, filtriranjem da se uklone nečistoće i taloženjem hidrokloridne soli suhim eterom. U.S. Patent No. 4,695,578, Example 1a, reports the preparation of ondansetron by alkylation of 2-methylimidazole with 2,3,4,9-tetrahydro-N,N,N,9-tetramethyl-4-oxo-1H-carbazole-3-methanaminium iodide. In this example, ondansetron was isolated as its hydrochloride salt by suspending the reaction product in a mixture of absolute ethanol and ethanolic HCl, heating the suspension, filtering to remove impurities, and precipitating the hydrochloride salt with dry ether.
U primjeru 10 '578 patenta, slobodna ondansetron baza je prevedena u dihidrat hidrokloridne soli otapanjem slobodne baze u smjesi izopropanola i vode te obrađivanjem koncentriranom klorovodičnom kiselinom. Nakon filtriranja pri povišenoj temperaturi ondansetron je istjeran iz otopine dodavanjem dodatnog izopropanola i hlađenjem. Dihidrat je dobiven kao bijela kristalinična krutina prekristaliziranjem iz 6 : 10 smjese vode i izopropanola. Ondansetron hidroklorid dihidrat dobiven prema primjeru 10 '573 patenta nazvan je forma A u ovom izlaganju. Praškasti uzorci forme A proizvode rendgenski difraktogram praškastog uzorka bitno jednak difraktogramu prikazanom na slici 1. In Example 10 of the '578 patent, the ondansetron free base was converted to the dihydrate hydrochloride salt by dissolving the free base in a mixture of isopropanol and water and treating with concentrated hydrochloric acid. After filtration at elevated temperature, ondansetron was forced out of solution by adding additional isopropanol and cooling. The dihydrate was obtained as a white crystalline solid by recrystallization from a 6:10 mixture of water and isopropanol. Ondansetron hydrochloride dihydrate obtained according to Example 10 of the '573 patent is referred to as Form A in this disclosure. Powder samples of Form A produce an X-ray diffraction pattern of the powder sample substantially identical to the diffraction pattern shown in Figure 1.
U. S. Patent No. 5,344/658 opisuje ondansetron koji ima određenu veličinu čestica i upotrebu takvog ondansetrona u farmaceutskoj kompoziciji. U.S. Patent No. 5,344/658 describes ondansetron having a particular particle size and the use of such ondansetron in a pharmaceutical composition.
Veličina čestica ondansetron hidroklorid dihidrata dobivenog kristalizacijom iz otapala smanjuje se njihovom desolvatacijom, na primjer zagrijavanjem, i onda izlaganjem desolvatiziranih kristala vlažnoj atmosferi. Zbirka kristala dobivenih ovim postupkom smanjivanja veličine čestica rečeno je da se sastoji isključivo od kristala veličine manje od 250 mikrona i da sadrži 80% ili više kristala veličine manje od 63 mikrona. Veličina kristala određena je analizom pomoću lijevka s mlazom zraka. The particle size of ondansetron hydrochloride dihydrate obtained by crystallization from a solvent is reduced by desolvating them, for example by heating, and then exposing the desolvated crystals to a humid atmosphere. A collection of crystals obtained by this particle size reduction process is said to consist exclusively of crystals less than 250 microns in size and to contain 80% or more crystals less than 63 microns in size. Crystal size was determined by analysis using an air jet funnel.
Prema '658 patentu, ondansetron hidroklorid dehidrat koji ima istu raspodjelu veličine čestica kao rehidrirani ondansetron hidroklorid također je pružen kao dio tog izuma. S obzirom da je opisan samo jedan postupak za dehidrataciju ondansetron hidroklorida u '658 patentu, dehidrat je očito prijelazni spoj spoj koji se rehidratizira u postupku smanjivanja veličine čestica. According to the '658 patent, ondansetron hydrochloride dehydrate having the same particle size distribution as rehydrated ondansetron hydrochloride is also provided as part of that invention. Since only one process for dehydrating ondansetron hydrochloride is described in the '658 patent, the dehydrate is clearly a transition compound compound that is rehydrated in the particle size reduction process.
U. S. Patenti br. 4,695,578 i 5,344,658 su ovdje uključeni putem reference. U.S. Patent Nos. 4,695,578 and 5,344,658 are incorporated herein by reference.
Otkriće nove polimorfne forme farmaceutski korisnog spoja pruža novu priliku za poboljšanje performansnih karakteristika produkta. Ono povećava ponudu tvari koji su znanstveniku za formulacije na raspolaganju za dizajniranje, na primjer, farmaceutske forme doziranja lijeka sa ciljanim profilom otpuštanja ili nekom drugom željenom karakteristikom. Sada je otkriveno šest novih polimorfnih formi i solvata ondansetron hidroklorida. The discovery of a new polymorphic form of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of the product. It increases the range of substances available to the formulation scientist to design, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. Six new polymorphic forms and solvates of ondansetron hydrochloride have now been discovered.
Sažetak izuma Summary of the invention
Jedan cilj predmetnog izuma je da pruži nove forme ondansetron hidroklorida i postupke za njihovo priređivanje. One object of the present invention is to provide novel forms of ondansetron hydrochloride and processes for their preparation.
U skladu s tim, predmetni izum pruža novi ondansetron hidroklorid monohidrat koji se može preparirati ili iz ondansetron hidroklorid dihidrata ili iz ondansetron slobodne baze prema postupcima izuma. Monohidrat se naziva forma A hidrokloridna sol uslijed sličnosti rendgenskih spektralnih karakteristika s poznatim dihidratom ondansetron hidroklorida. Accordingly, the present invention provides a novel ondansetron hydrochloride monohydrate which can be prepared either from ondansetron hydrochloride dihydrate or from ondansetron free base according to the methods of the invention. The monohydrate is called form A hydrochloride salt due to the similarity of the X-ray spectral characteristics with the known dihydrate of ondansetron hydrochloride.
Izum dalje pruža novu bezvodnu formu ondansetron hidroklorida koja je nazvana forma B. Forma B ima prednost svojstva veličine čestica i samo je lagano higroskopna. Forma B može se prirediti iz ondansetron hidroklorida forma A i iz ondansetron slobodne baze. The invention further provides a new anhydrous form of ondansetron hydrochloride which is named Form B. Form B has the advantage of particle size properties and is only slightly hygroscopic. Form B can be prepared from ondansetron hydrochloride form A and from ondansetron free base.
Također su iznesene dodatne ondansetron hidroklorid forme nazvane forme C, D i H te postupci za njihovu pripremu. Additional ondansetron hydrochloride forms called Forms C, D and H and processes for their preparation are also disclosed.
Još dalje, predmetni izum pruža izopropanolate i metanolate ondansetron hidroklorida i postupke za njihovu pripremu. Still further, the present invention provides isopropanolates and methanolates of ondansetron hydrochloride and processes for their preparation.
Bezvodne forme ondansetron hidroklorida i hidrati predmetnog izuma su prikladne za upotrebu u farmaceutskim kompozicijama formuliranim za sprečavanje postoperativne mučnine i mučnina koja se javlja za vrijeme kemoterapije. The anhydrous forms of ondansetron hydrochloride and hydrates of the present invention are suitable for use in pharmaceutical compositions formulated to prevent postoperative nausea and nausea occurring during chemotherapy.
Kratak opis crteža Brief description of the drawing
Slika 1 je rendgenski difraktogram praškastog uzorka ondansetron hidroklorid forme A. Figure 1 is an X-ray diffractogram of a powder sample of Ondansetron Hydrochloride Form A.
Slika 2 je rendgenski difraktogram praškastog uzorka ondansetron hidroklorid forme B. Figure 2 is an X-ray diffractogram of a powder sample of Ondansetron Hydrochloride Form B.
Slika 3 je rendgenski difraktogram praškastog uzorka ondansetron hidroklorid forme C. Figure 3 is an X-ray diffractogram of a powder sample of ondansetron hydrochloride form C.
Slika 4 je rendgenski difraktogram praškastog uzorka ondansetron hidroklorid forme E. Figure 4 is an X-ray diffractogram of a powder sample of Ondansetron Hydrochloride Form E.
Slika 5 je profil termogravimetrijske analize ondansetron hidroklorid forme E. Figure 5 is a thermogravimetric analysis profile of Ondansetron Hydrochloride Form E.
Slika 6 je rendgenski difraktogram praškastog uzorka ondansetron hidroklorid forme H. Figure 6 is an X-ray diffractogram of a powder sample of ondansetron hydrochloride form H.
Slika 7 je rendgenski difraktogram praškastog uzorka ondansetron hidroklorid forme I. Figure 7 is an X-ray diffractogram of a powder sample of Ondansetron Hydrochloride Form I.
Slika 8 je profil termogravimetrijske analize ondansetron hidroklorid forme I. Figure 8 is a thermogravimetric analysis profile of ondansetron hydrochloride form I.
Detaljan opis izuma Detailed description of the invention
Ondansetron hidroklorid monohidrat Ondansetron hydrochloride monohydrate
U jednom aspektu predmetni izum pruža Ondansetron hidroklorid monohidrat. Nađeno je da monohidrat ima jednaku jediničnu ćeliju kao hidroklorid dihidrat dobiven prema postupku primjera 10 u U. S. Patentu No. 4,695,578 koji je nazvan forma A u ovom izlaganju. Dokaz da monohidrat zauzima i/ili zadržava kristalnu formu A (ovisno o postupku kojim je priređen) može se naći u rendgenskom difraktogramu dobivenom za monohidrat koji vrlo blizu odgovara difraktogramu dobivenom za uzorke forma A dihidrata. Ovo je čvrsti dokaz da su kristalne strukture približno jednake. Ondansetron hidroklorid forme A karakteriziran je jakom difrakcijom na 23.3 ± 0.2 stupnjeva dva theta i drugim difrakcijskim maksimumima na 6.1, 12.4, 17.0, 18.3, 19.2, 20.3, 20.9, 24.1, 25.8, 28.1, 30.3 ± 0.2 stupnjeva dva theta. Rendgenski difraktogram praha uzorka forma A monohidrata priložen je kao slika 1. Ondansetron hidroklorid forma A koja se izolira postupcima predmetnog izuma su tipično veliki kristali pločastog oblika. In one aspect, the present invention provides Ondansetron hydrochloride monohydrate. The monohydrate was found to have the same unit cell as the hydrochloride dihydrate obtained by the procedure of Example 10 in U.S. Patent No. 4,695,578 which is referred to as Form A in this disclosure. Evidence that the monohydrate occupies and/or retains crystalline form A (depending on the process by which it was prepared) can be found in the X-ray diffractogram obtained for the monohydrate which very closely matches the diffractogram obtained for the dihydrate form A samples. This is strong evidence that the crystal structures are approximately equal. Ondansetron hydrochloride form A is characterized by a strong diffraction at 23.3 ± 0.2 degrees two theta and other diffraction maxima at 6.1, 12.4, 17.0, 18.3, 19.2, 20.3, 20.9, 24.1, 25.8, 28.1, 30.3 ± 0.2 degrees two theta. The powder X-ray diffractogram of a sample of Form A monohydrate is attached as Figure 1. Ondansetron hydrochloride Form A which is isolated by the methods of the present invention are typically large, plate-shaped crystals.
Ondansetron hidroklorid forma A može postojati u obliku prijelaznih stupnjeva hidratacije između razine monohidrata i dihidrata. Ondansetron hidroklorid forma A može se kristalizirati u ovdje iznesenim uvjetima uz varirajuće ali predvidive količine vode. Količina prisutne vode u bilo kojoj od ondansetron hidratnih formi predmetnog izuma može se odrediti na uobičajeni način kao što je Karl Fisher metoda. Ondansetron hydrochloride form A can exist in the form of intermediate hydration levels between the monohydrate and dihydrate levels. Ondansetron hydrochloride form A can be crystallized under the conditions set forth herein with varying but predictable amounts of water. The amount of water present in any of the ondansetron hydrate forms of the present invention can be determined by a conventional method such as the Karl Fisher method.
Izlaganje svježe priređenih uzoraka ondansetron hidroklorid forma A monohidrata atmosferi s kontroliranom vlažnosti, kao što je 60% relativna vlažnost ili više, uzrokuje da se količina vode u kristalima ubrzano povećava dok se ne postigne razina dihidratne količine vode od oko 10.0%. Upijanje vode obično se događa unutar nekoliko sati ili najviše preko noći. Lakoća dehidratacije ondansetron hidroklorid forma A dihidrata do nižeg stanja hidratacije i sposobnosti da se rehidratizira u vlažnoj atmosferi do razine dihidrata pokazuje da je najmanje jedna od molekula vode kristalizacije u ondansetron hidroklorid dihidratu labilna. Exposure of freshly prepared samples of ondansetron hydrochloride form A monohydrate to a controlled humidity atmosphere, such as 60% relative humidity or higher, causes the amount of water in the crystals to increase rapidly until a dihydrate water level of about 10.0% is reached. Water absorption usually occurs within a few hours or overnight at most. The ease of dehydration of ondansetron hydrochloride form A dihydrate to a lower hydration state and the ability to rehydrate in a humid atmosphere to the dihydrate level indicates that at least one of the molecules of water of crystallization in ondansetron hydrochloride dihydrate is labile.
Nakon sušenja ondansetron hidroklorid forma A dihidrata u vakuumskoj peći pri 90°C 12 sati, ondansetron forma A monohidrat može se dehidrirati do bitno bezvodnog stanja sa sadržajem vode od 1.3% ili manje. Ondansetron forma A s takvim niskim sadržajem vode također zadržava kristalnu strukturu ondansetron hidroklorid forme A i stoga je karakteriziran rendgenskim difraktorgramom praha ondansetron hidroklorid forme A. Visoko dehidratizirana ondansetron hidroklorid forma A rehidratizira se nakon izlaganja 50% do 60% relativnoj vlažnosti i pretvara se u ondansetron hidroklorid dihidrat (10.0% vode). After drying ondansetron hydrochloride form A dihydrate in a vacuum oven at 90°C for 12 hours, ondansetron form A monohydrate can be dehydrated to an essentially anhydrous state with a water content of 1.3% or less. Ondansetron Form A with such a low water content also retains the crystalline structure of Ondansetron Hydrochloride Form A and is therefore characterized by the X-ray diffractogram of Ondansetron Hydrochloride Form A powder. Highly dehydrated Ondansetron Hydrochloride Form A rehydrates upon exposure to 50% to 60% relative humidity and is converted to ondansetron hydrochloride dihydrate (10.0% water).
Preparacija ondansetron hidroklorid forma A monohidrata iz ondansetron hidroklorid forma A dihidrata Preparation of ondansetron hydrochloride form A monohydrate from ondansetron hydrochloride form A dihydrate
Ondansetron hidroklorid forma A monohidrat može se prirediti iz ondansetron hidroklorid forma A dihidrata. Dihidrat se suspendira ili razmulji u tekućem mediju vodene otopine etanola. Preferirani tekući mediji su smjese od oko 50% etanol/voda do oko 96% etanol/voda. Nema direktne povezanosti između razine hidratacije dobivene forme A i udjela vode u tekućem mediju. Smjese vode i etanola unutar raspona daju formu A s mjerenim sadržajem vode u skladu s računatim sadržajem vode ondansetron hidroklorid monohidrata od 5.18 %, kao što se može vidjeti, na primjer, uspoređivanjem primjera 14 i 15 dolje. Ondansetron hydrochloride form A monohydrate can be prepared from ondansetron hydrochloride form A dihydrate. The dihydrate is suspended or slurried in a liquid medium of an aqueous ethanol solution. Preferred liquid media are mixtures of about 50% ethanol/water to about 96% ethanol/water. There is no direct relationship between the level of hydration of the obtained form A and the proportion of water in the liquid medium. Mixtures of water and ethanol within the range give Form A with a measured water content consistent with the calculated ondansetron hydrochloride monohydrate water content of 5.18%, as can be seen, for example, by comparing Examples 14 and 15 below.
Suspenzija ili muljevita smjesa forme A dihidrata se preferirano zagrijava uz refluks da se ubrza djelomična dehidratacija do koje dolazi u ovim etanol i voda smjesama. Forma A monohidrat može se pogodno odvojiti od tekućeg medija hlađenjem i filtriranjem suspenzije. The suspension or slurry of Form A dihydrate is preferably heated at reflux to accelerate the partial dehydration that occurs in these ethanol and water mixtures. Form A monohydrate can conveniently be separated from the liquid medium by cooling and filtering the suspension.
Postupak je dalje ilustriran primjerima 12 - 19. The procedure is further illustrated by examples 12 - 19.
Primjeri 18 i 19 pokazuju da se monohidrat također može dobiti primjenom izvjesnih nevodenih tekućih medija, određenije etanol/izopropanol i etanol/toluen smjesa. Examples 18 and 19 show that the monohydrate can also be obtained using certain non-aqueous liquid media, more specifically ethanol/isopropanol and ethanol/toluene mixtures.
Međutim, takve smjese općenito uzrokuju kristaliziranje ondansetron hidroklorid forme A u stanju preijelazne hidratiziranosti između monohidrata i dihidrata, kako je prikazano primjerima 20 - 25. Ondansetron hidroklorid sa sadržajem vode između 6 i 9 %, prijelaz između monohidrata (5.18%) i dihidrata (9.85%) se reproducibilno dobiva prema postupcima primjera 20 - 25. However, such mixtures generally cause ondansetron hydrochloride Form A to crystallize in a transition state of hydration between monohydrate and dihydrate, as shown in Examples 20 - 25. Ondansetron hydrochloride with water content between 6 and 9%, transition between monohydrate (5.18%) and dihydrate (9.85 %) is reproducibly obtained according to the procedures of examples 20 - 25.
Preparacija ondansetron hidroklorid forme A iz ondansetron baze Preparation of ondansetron hydrochloride form A from ondansetron base
Poznati postupci za pripremu ondansetron hidroklorid forme A koristili su, kao otapalo, smjese vode i izopropanola i voda/izopropanol/octena kiselina za stvaranje ondansetron hidrokloridne soli iz slobodne baze. Ovi sistemi otapala dosljedno uzrokuju da ondansetron hidroklorid kristalitira kao dihidrat. Known procedures for the preparation of ondansetron hydrochloride form A used, as solvent, mixtures of water and isopropanol and water/isopropanol/acetic acid to form the ondansetron hydrochloride salt from the free base. These solvent systems consistently cause ondansetron hydrochloride to crystallize as the dihydrate.
Predmetni izum pruža novi postupak za pripremu ondansetron hidroklorid forme A iz ondansetron slobodne baze. U ovom novom postupku slobodna baza se suspendira u apsolutnom etanolu i obradi laganim suviškom bezvodnog HCl. HCl može se dobiti ili kao plin ili otopljen u organskom otapalu kao što je apsolutni etanol, toluen, metil etil keton, izopropanol ili eter. Suspenzija se preferirano zagrijava uz refluks da se ubrza otapanje slobodne baze i njeno prevođenje u HCl sol. Forma A dihidrat se prikladno dobiva hlađenjem otopine da se potakne kristalizacija i filtriranjem da se odvoji otapalo i bilo koje nečistoće. Postupak je dalje prikazan primjerima 1 - 11. The present invention provides a novel process for the preparation of ondansetron hydrochloride form A from ondansetron free base. In this new procedure, the free base is suspended in absolute ethanol and treated with a slight excess of anhydrous HCl. HCl can be obtained either as a gas or dissolved in an organic solvent such as absolute ethanol, toluene, methyl ethyl ketone, isopropanol or ether. The suspension is preferably heated at reflux to accelerate the dissolution of the free base and its conversion to the HCl salt. Form A dihydrate is conveniently obtained by cooling the solution to promote crystallization and filtering to remove the solvent and any impurities. The procedure is further illustrated by examples 1 - 11.
Mi smo također našli da korištenjem kloriranog otapala kao što je kloroform, uz mogućnost smjese s vodom, možemo dobiti ondansetron hidroklorid kao monohidrat, kako je dalje prikazano u primjerima 8 - 11. We have also found that using a chlorinated solvent such as chloroform, with the possibility of mixing with water, we can obtain ondansetron hydrochloride as the monohydrate, as further shown in Examples 8-11.
Bezvodna ondansetron hidroklorid forma B Anhydrous ondansetron hydrochloride form B
Predmetni izum pruža novu formu ondansetron hidroklorida označenu bezvodna ondansetron hidroklorid forma B i postupke za pripremu bezvodne ondansetron hidroklorid forme B. Bezvodna ondansetron hidroklorid forma B može se preparirati polaženjem od ondansetron hidroklorid forma A ili polaženjem od ondansetron baze. The present invention provides a new form of ondansetron hydrochloride designated anhydrous ondansetron hydrochloride form B and methods for the preparation of anhydrous ondansetron hydrochloride form B. Anhydrous ondansetron hydrochloride form B can be prepared starting from ondansetron hydrochloride form A or starting from an ondansetron base.
Bezvodna ondansetron hidroklorid forma B karakterizirana je jakim maksimumom rendgenske difrakcije praškastog uzorka na 11.9 ± 0.2 stupnjeva dva theta i maksimumima rendgenske difrakcije praškastog uzorka na 10.5, 13.0, 13.5, 15.1, 20.9, 22.7, 24.0, 25.7 ± 0.2 stupnjeva dva theta. Rendgenski digraktogram uzorka forme B priložen je kao slika 2. U našim rukama bezvodna ondansetron hidroklorid forma B javlja se kao fini prašak primarno sastavljen od malih iglica i štapića. Anhydrous ondansetron hydrochloride form B is characterized by a strong X-ray diffraction peak of the powder sample at 11.9 ± 0.2 degrees two theta and peaks of X-ray diffraction of the powder sample at 10.5, 13.0, 13.5, 15.1, 20.9, 22.7, 24.0, 25.7 ± 0.2 degrees two theta. An X-ray digractogram of a sample of Form B is attached as Figure 2. In our hands, anhydrous ondansetron hydrochloride Form B appears as a fine powder primarily composed of small needles and rods.
Bezvodna ondansetron hidroklorid forma B predmetnog izuma upija do 2% vlage kada se izloži 60% relativnoj vlažnosti. Apsorbirana voda u kristalima nije unutar kristalne strukture vodene forme kao hidratna voda. Odsutnost hidratne vode unutar kristalne strukture može se pratiti uobičajenim postupcima, kao što je PXRD. Korištenjem tehnika rendgenske difrakcije praškastog uzorka pokazana je odsutnost hidratne vode uslijed odsutnosti ondansetron hidroklorid forme A u uzorku. Prisutnost forme A je pokazana pojavom jakog maksimuma na 12.3° 29 u rendgenskom difraktogramu uzorka. Anhydrous ondansetron hydrochloride form B of the present invention absorbs up to 2% moisture when exposed to 60% relative humidity. The absorbed water in the crystals is not within the crystal structure of the aqueous form as hydrate water. The absence of hydrate water within the crystal structure can be monitored by conventional methods, such as PXRD. The use of X-ray diffraction techniques of the powder sample showed the absence of hydrated water due to the absence of ondansetron hydrochloride form A in the sample. The presence of form A is shown by the appearance of a strong maximum at 12.3° 29 in the X-ray diffractogram of the sample.
Predmetni izum također pruža preparaciju malih čestica ondansetron hidroklorid forme B što ima prednost da ne zahtijeva skupe postupke koji troše veliku količinu energije, kao što je masovno mljevenje, ili složene procese dehidratacije i rehidratacije kako bi se postiglo željeno smanjivanje veličine čestica. Raspodjela veličine čestica ondansetron hidroklorid forme B, koji je karakteriziran time da ima male čestice oblika iglica/štapić uz maksimalnu veličinu do 200 mikrona, tipično s d(0.9) do 140 mikrona, d(0.5) do 30 mikrona, d(0.1) do 2 mikrona. Preferirano, vrijednost d(0.9) je do 40 mikrona. The present invention also provides the preparation of small particles of ondansetron hydrochloride form B which has the advantage of not requiring expensive, energy-intensive processes, such as mass milling, or complex dehydration and rehydration processes to achieve the desired particle size reduction. Particle size distribution of ondansetron hydrochloride form B, which is characterized by having small needle/rod shaped particles with a maximum size of up to 200 microns, typically with d(0.9) to 140 microns, d(0.5) to 30 microns, d(0.1) to 2 micron. Preferably, the d(0.9) value is up to 40 microns.
Preparacija bezvodne ondansetron hidroklorid forme B iz ondansetron hidroklorid forme A Preparation of anhydrous ondansetron hydrochloride form B from ondansetron hydrochloride form A
Postupcima predmetnog izuma bezvodna ondansetron hidroklorid forma B može se prirediti iz ondansetron hidroklorid forme A obrađivanjem suhim C1-C4 alkoholnim otapalom kao etanol, izopropanol i 1-butanol, ili ketonsko.otapalo kao aceton i metil etil keton ("MEK"). Kada se predmetni postupak za pripremu bezvodne ondansetron hidroklorid forme B provodi na sobnoj temperaturi, preferirano otapalo je aceton, metil etil keton, apsolutni etanol ili smjesa izopropanola i etanola (preferirano apsolutni etanol se također koristi u smjesi). Kako se koristi u ovom izlaganju apsolutni etanol se odnosi na etanol koji ne sadrži više od 0.5% vode. Preferirano izopropanol i etanol smjesa ima omjer 40 : 65 (v/v) izopropanola prema etanolu. Kada se predmetni postupak za pripremu bezvodne ondansetron hidroklorid forme B provodi na povišenim temperaturama, preferirano otapalo je 1-butanol i smjesa se zagrijava uz refluks. By the processes of the present invention, anhydrous ondansetron hydrochloride form B can be prepared from ondansetron hydrochloride form A by treatment with a dry C1-C4 alcoholic solvent such as ethanol, isopropanol and 1-butanol, or a ketone solvent such as acetone and methyl ethyl ketone ("MEK"). When the subject process for the preparation of anhydrous ondansetron hydrochloride form B is carried out at room temperature, the preferred solvent is acetone, methyl ethyl ketone, absolute ethanol or a mixture of isopropanol and ethanol (preferably absolute ethanol is also used in the mixture). As used in this disclosure, absolute ethanol refers to ethanol containing no more than 0.5% water. Preferably, the isopropanol and ethanol mixture has a ratio of 40:65 (v/v) isopropanol to ethanol. When the subject process for the preparation of anhydrous ondansetron hydrochloride form B is carried out at elevated temperatures, the preferred solvent is 1-butanol and the mixture is heated to reflux.
Postupak predmetnog izuma pruža iznenađujući rezultat da se ondansetron hidroklorid forma A može pretvoriti u bezvodnu ondansetron hidroklorid formu B razmuljivanjem ondansetron hidroklorid forme A u apsolutnom etanolu, preferirano na sobnoj temperaturi (to znači oko 20°C), omogućava jednostavnu i brzu transformaciju ondansetron hidroklorid forme A u bezvodnu ondansetron hidroklorid formu B. Transformacija ondansetron hidroklorid forme A u bezvodnu ondansetron hidroklorid formu B završi se kroz između nekoliko sati do dva dana i više, ovisno o različitim parametrima kao veličina čestica, relativna količina otapala, temperatura. Tipično, potpuno konverzija zahtijeva između 24 i 48 sati pri sobnoj temperaturi. Reakcija se treba provoditi u suhim uvjetima. Provođenje reakcije ili u suhom dušiku ili atmosferi argona ili u tikvici koja ima vezu sa zrakom kroz cjevčicu za sušenje sa CaCl2 pruža zadovoljavajuće suhe uvjete. The process of the present invention provides the surprising result that ondansetron hydrochloride form A can be converted into anhydrous ondansetron hydrochloride form B by emulsifying ondansetron hydrochloride form A in absolute ethanol, preferably at room temperature (that means about 20°C), enabling a simple and rapid transformation of ondansetron hydrochloride form A to anhydrous ondansetron hydrochloride form B. The transformation of ondansetron hydrochloride form A to anhydrous ondansetron hydrochloride form B is completed within a few hours to two days or more, depending on various parameters such as particle size, relative amount of solvent, temperature. Typically, complete conversion requires between 24 and 48 hours at room temperature. The reaction should be carried out under dry conditions. Conducting the reaction either in a dry nitrogen or argon atmosphere or in a flask connected to air through a drying tube with CaCl2 provides satisfactorily dry conditions.
Bezvodna ondansetron hidroklorid forma B može se također preparirati propuštanjem plinovitog HCl kroz otopinu ondansetron baze u toluenu uz refluks. Anhydrous ondansetron hydrochloride form B can also be prepared by passing HCl gas through a solution of ondansetron base in toluene under reflux.
Preparacija bezvodne ondansetron hidroklorid forme B iz ondansetron baze Preparation of anhydrous ondansetron hydrochloride form B from ondansetron base
Predmetni izum također pruža postupak za pripremu bezvodne ondansetron hidroklorid forme B iz ondansetron slobodne baze. Predmetnim postupcima ondansetron baza reagira sa suhim HCl u suhom organskom otapalu. HCl može se dobiti ili kao plin ili otopljen u suhom organskom otapalu kao što je apsolutni etanol, toluen, metil etil keton, izopropanol ili eter. Nakon završetka reakcije, bezvodna ondansetron hidroklorid forma B može se izolirati filtriranjem. Forma B kristali imaju karakterističan oblik iglica. The present invention also provides a process for the preparation of anhydrous ondansetron hydrochloride form B from ondansetron free base. In the subject procedures, the ondansetron base reacts with dry HCl in a dry organic solvent. HCl can be obtained either as a gas or dissolved in a dry organic solvent such as absolute ethanol, toluene, methyl ethyl ketone, isopropanol or ether. After completion of the reaction, anhydrous ondansetron hydrochloride form B can be isolated by filtration. Form B crystals have a characteristic needle shape.
Preparacija bezvodne ondansetron hidroklorid forme B predmetnim postupkom omogućena je činjenicom da su otapalo (etanol) i otopina HCl/etanol suhi. Tako, na ovaj način forma A ne nastaje za vrijeme reakcije. Reakcija se može provoditi pri sobnoj temperaturi (rt) ili uz refluks. Pri sobnoj temperaturi reakcija je heterogena i dovodi do bezvodne ondansetron hidroklorid forme B s raspodjelom male veličine čestica. Kada se provodi uz refluks, reakcija je homogena i može se tako obraditi aktivnim ugljenom da se dobije čistija sol. Nakon vrućeg filtriranja da se ukloni ugljen, ondansetron hidroklorid forma B može se dobiti hlađenjem filtrata do sobne temperature i sakupljanjem istaložene forme B filtriranjem. Raspodjela veličine čestica može se jednostavno kontrolirati mijenjanjem parametara kristalizacije, uključivši kontrolirano hlađenje. The preparation of anhydrous ondansetron hydrochloride form B by the method in question is made possible by the fact that the solvent (ethanol) and the HCl/ethanol solution are dry. Thus, in this way form A is not formed during the reaction. The reaction can be carried out at room temperature (rt) or under reflux. At room temperature, the reaction is heterogeneous and leads to anhydrous ondansetron hydrochloride form B with a small particle size distribution. When carried out under reflux, the reaction is homogeneous and can thus be treated with activated carbon to obtain a purer salt. After hot filtration to remove carbon, ondansetron hydrochloride form B can be obtained by cooling the filtrate to room temperature and collecting the precipitated form B by filtration. The particle size distribution can be easily controlled by changing the crystallization parameters, including controlled cooling.
Ondansetron hidroklorid forma C Ondansetron hydrochloride form C
Predmetni izum pruža novu formu o.ndansetron hidroklorida označenu ondansetron hidroklorid forma C i postupke za pripremu ondansetron hidroklorid forme C. Ova forma karakterizirana je jakim maksimumima rendgenske difrakcije praškastog uzorka na 6.3, 24.4, stupnjeva dva theta i drugim tipičnim maksimumima na 9.2, 10.2, 13.1, 16.9 stupnjeva dva theta. Rendgenski difraktogram uzorka forme C priložen je kao slika 3. Ova forma može se dobiti otapanjem ondansetron hidroklorid forme A u etanolu uz refluks nakon dodavanja HCl (plinovitog ili u otopini). Nakon hlađenja otopine, talog se filtrira i matičnica se upari pod sniženim pritiskom. Ondansetron hidroklorid forma C nastaje iz ove krutine dobivene nakon uparavanja. Ondansetron hidroklorid forma C je higroskopna i može sadržavati do 10% vode. The present invention provides a new form of ondansetron hydrochloride designated ondansetron hydrochloride form C and methods for the preparation of ondansetron hydrochloride form C. This form is characterized by strong powder X-ray diffraction peaks at 6.3, 24.4, degrees two theta and other typical peaks at 9.2, 10.2, 13.1, 16.9 degrees two theta. An X-ray diffraction pattern of a sample of Form C is attached as Figure 3. This form can be obtained by dissolving ondansetron hydrochloride Form A in ethanol at reflux after addition of HCl (gaseous or in solution). After cooling the solution, the precipitate is filtered and the mother liquor is evaporated under reduced pressure. Ondansetron hydrochloride form C is formed from this solid obtained after evaporation. Ondansetron hydrochloride form C is hygroscopic and may contain up to 10% water.
Ondansetron hidroklorid forma D Ondansetron Hydrochloride Form D
Predmetni izum pruža novu formu ondansetron hidroklorida označenu ondansetron hidroklorid forma D. Ova forma može se dobiti kao smjesa s ondansetron hidroklorid formom C. Ondansetron hidroklorid forma D se dobiva dispergiranjem ondansetron hidroklorid forme A u oko l mililitru ksilena po gramu forme A, onda taljenjem disperzije na temperaturi iznad 150°C, preferirano iznad 180°C i ulijevanjem taline u hladni alkohol, preferirano oko 10 mililitara etanola po gramu disperzije. Alkohol može biti na temperaturi ispod sobne temperature do sobne temperature, preferirano na oko 10°C. The present invention provides a new form of ondansetron hydrochloride designated ondansetron hydrochloride form D. This form can be obtained as a mixture with ondansetron hydrochloride form C. Ondansetron hydrochloride form D is obtained by dispersing ondansetron hydrochloride form A in about 1 milliliter of xylene per gram of form A, then melting the dispersion at a temperature above 150°C, preferably above 180°C and by pouring the melt into cold alcohol, preferably about 10 milliliters of ethanol per gram of dispersion. The alcohol can be at a temperature below room temperature to room temperature, preferably around 10°C.
Ondansetron hidroklorid forma D karakterizirana je maksimumima rendgenske difrakcije praškastog uzorka na 8.3, 14.0, 14.8, 25.5 stupnjeva dva theta. Ondansetron hydrochloride form D is characterized by X-ray diffraction maxima of the powder sample at 8.3, 14.0, 14.8, 25.5 degrees two theta.
Ondansetron hidroklorid forma E Ondansetron hydrochloride form E
Predmetni izum pruža novu formu Ondansetron hidroklorida označenu ondansetron hidroklorid forma E i postupke za pripremu ondansetron hidroklorid forme E. The subject invention provides a new form of Ondansetron Hydrochloride designated as Ondansetron Hydrochloride Form E and processes for the preparation of Ondansetron Hydrochloride Form E.
Ondansetron hidroklorid forma E karakterizirana je jakim maksimumom rendgenske difrakcije praškastog uzorka na 7.4 stupnjeva dva theta i drugim tipičnim maksimumima na 6.3, 10.5, 11.2, 12.3, 13.0, 14.5, 15.9, 17.0, 20.1, 20.8, 24.5, 26.2, 27.2 stupnjeva dva theta. Rendgenski difraktogram uzorka forme E priložen je kao slika 4. Ondansetron hidroklorid forma E sadrži 1.8% -2.0 % vode, kako je mjereno Karl Fisher metodom. Ova stehiometrije ka vrijednost odgovara 1/3 molekule vode po molekuli ondansetron hidroklorida (teoretska vrijednost: 1.8%). Ondansetron hydrochloride form E is characterized by a strong X-ray diffraction maximum of the powder sample at 7.4 degrees two theta and other typical maxima at 6.3, 10.5, 11.2, 12.3, 13.0, 14.5, 15.9, 17.0, 20.1, 20.8, 24.5, 26.2, 27.2 degrees two theta. . An X-ray diffractogram of a sample of Form E is attached as Figure 4. Ondansetron Hydrochloride Form E contains 1.8%-2.0% water, as measured by the Karl Fisher method. This stoichiometry ka value corresponds to 1/3 molecule of water per molecule of ondansetron hydrochloride (theoretical value: 1.8%).
Iznenađujuće je otkriveno da obrađivanje ondansetron hidroklorid forme A u izopropanolu dovodi do stvaranja ondansetron hidroklorid forme E. Ondansetron hidroklorid, preferirano forma A dihidrat, može se obraditi u izopropanolu pri sobnoj temperaturi ili pri temperaturi refluksa da se dobije ondansetron hidroklorid forma E. It has surprisingly been found that treatment of ondansetron hydrochloride form A in isopropanol leads to the formation of ondansetron hydrochloride form E. Ondansetron hydrochloride, preferably form A dihydrate, can be treated in isopropanol at room temperature or at reflux temperature to give ondansetron hydrochloride form E.
Nađeno je da ondansetron hidroklorid forme E koji je dobiven obrađivanjem ondansetron hidroklorid forme A u izopropanolu uključuje količine izopropanola od oko 8 - 10 % ili 14 %. Tipična TGA krivulja ondansetron hidroklorid forme E (slika 5) pokazuje gubitak težine od oko 2 % do oko 120°C i oštri gubitak težine na oko 150°C od 9 % ili 14 %. Prema stehiometrijskom računu, ondansetron hidroklorid forma E može postojati kao monosolvat izopropanola ili hemisolvat izopropanola (očekivana stehiometrijska vrijednost izopropanol hemisolvata je 8.4% i očekivana stehiometrijska vrijednost izopropanol monosolvata je 15.4%). Također je nađeno da ondansetron hidroklorid propanolat forma E, kada je izložena relativnoj vlažnosti do 60% kroz jedan tjedan može sadržavati do 10% vode bez promjene kristalne strukture. Ondansetron hydrochloride form E which was obtained by treating ondansetron hydrochloride form A in isopropanol was found to include amounts of isopropanol of about 8-10% or 14%. A typical TGA curve of ondansetron hydrochloride Form E (Figure 5) shows a weight loss of about 2% up to about 120°C and a sharp weight loss at about 150°C of 9% or 14%. According to stoichiometric calculation, ondansetron hydrochloride form E can exist as isopropanol monosolvate or isopropanol hemisolvate (expected stoichiometric value of isopropanol hemisolvate is 8.4% and expected stoichiometric value of isopropanol monosolvate is 15.4%). It was also found that ondansetron hydrochloride propanolate form E, when exposed to relative humidity up to 60% for one week, can contain up to 10% water without changing the crystal structure.
Ondansetron hidroklorid forma H Ondansetron hydrochloride form H
Predmetni izum pruža novu formu ondansetron hidroklorida označenu ondansetron hidroklorid forma H i postupke za pripremu ondansetron hidroklorid forme H. Postupcima predmetnog izuma ondansetron hidroklorid forma H može se dobiti otapanjem ondansetron baze u etanolu, preferirano apsolutnom etanolu, dodavanjem količine otopine etanol/kloridna kiselina dovoljne da dobavi 1,5 ekvivalenata HCl i taloženjem ondansetron hidroklorid forme H dodavanjem t-butil metil etera ili dietil etera (preferirano suhog i svježe destiliranog) da se omogući taloženje (l g/86 ml). Otopina ondansetron baze u apsolutnom etanolu može se zagrijati iznad sobne temperature, preferirano na oko 45°C. Ondansetron hidroklorid forma H može se također dobiti kao smjesa s bezvodnom ondansetron hidroklorid formom B kada se koristi etil eter kao otapalo. Izoliorana ondansetron hidroklorid forma H imala je saržaj oko 2% vode. The present invention provides a new form of ondansetron hydrochloride designated ondansetron hydrochloride form H and processes for the preparation of ondansetron hydrochloride form H. By the processes of the present invention, ondansetron hydrochloride form H can be obtained by dissolving ondansetron base in ethanol, preferably absolute ethanol, adding an amount of ethanol/hydrochloric acid solution sufficient to add 1.5 equivalents of HCl and precipitate ondansetron hydrochloride Form H by adding t-butyl methyl ether or diethyl ether (preferably dry and freshly distilled) to allow precipitation (1 g/86 ml). A solution of ondansetron base in absolute ethanol can be warmed above room temperature, preferably to about 45°C. Ondansetron hydrochloride form H can also be obtained as a mixture with anhydrous ondansetron hydrochloride form B when ethyl ether is used as the solvent. Isolated ondansetron hydrochloride form H had a composition of about 2% water.
Ondansetron hidroklorid forma H karakterizirana je jedinstvenim maksimumima rendgenske difrakcije praškastog uzorka na 7.8, 14.0, 14.8, 24.7, 25.6 stupnjeva dva theta. Rendgenski difraktogram uzorka forme H priložen je kao slika 6. Ondansetron hydrochloride form H is characterized by unique X-ray diffraction maxima of the powder sample at 7.8, 14.0, 14.8, 24.7, 25.6 degrees two theta. The X-ray diffractogram of the Form H sample is attached as Figure 6.
Ondansetron hidroklorid forma I Ondansetron Hydrochloride Form I
Predmetni izum pruža novu formu ondansetron hidroklorida označenu ondansetron hidroklorid forma I i postupke -za pripremu ondansetron hidroklorid forme I. Ondansetron hidroklorid, ili forma A ili bezvodni anhidrous, može se obrađivati u parama metanola kroz period od nekoliko dana do dva tjedna da se dobije ondansetron hidroklorid forma I. Kako bi se postigla konverzija većine uzorka u formu I, potreban je period od dva tjedna. Ondansetron hidroklorid forma I sadrži 3.1% vode, kako je mjereno Karl Fisher metodom. Ova stehiometrijska vrijednost odgovara 1/2 molekule vode po molekuli ondansetron hidroklorida (teoretska vrijednost: 2.5%). Ondansetron hidroklorid forma I sadrži metanol do 10% što grubo odgovara monometanolatnoj stehiometrijskoj vrijednosti od oko 9%. The present invention provides a new form of ondansetron hydrochloride designated as ondansetron hydrochloride form I and processes for the preparation of ondansetron hydrochloride form I. Ondansetron hydrochloride, either form A or anhydrous anhydrous, can be processed in methanol vapors for a period of several days to two weeks to obtain ondansetron hydrochloride form I. In order to achieve the conversion of the majority of the sample to form I, a period of two weeks is required. Ondansetron hydrochloride form I contains 3.1% water, as measured by the Karl Fisher method. This stoichiometric value corresponds to 1/2 molecule of water per molecule of ondansetron hydrochloride (theoretical value: 2.5%). Ondansetron hydrochloride form I contains up to 10% methanol, which roughly corresponds to a monomethanolate stoichiometric value of about 9%.
Ondansetron hidroklorid forma I karakterizirana je jakim maksimumom rendgenske difrakcije praškastog uzorka na 24.9 stupnjeva dva theta i drugim XRD maksimumima na 6.9, 8.2, 8.7, 9.1, 9.3, 9.9, 11.1, 11.6, 13.8, 16.1, 16.9, 17.9, 21.1, 22.7, 25.7, 26.6, 27.4, 27.9 +_ 0.2 stupnjeva dva theta. Rendgenski difraktogram uzorka forme I priložen je kao slika 7. Tipična termogravimetrijska krivulja forme I (slika 8) pokazuje gubitak težine od oko 10% u rasponu od sobne temperature do oko 130°C. Ondansetron hydrochloride form I is characterized by a strong X-ray diffraction maximum of the powder sample at 24.9 degrees two theta and other XRD maxima at 6.9, 8.2, 8.7, 9.1, 9.3, 9.9, 11.1, 11.6, 13.8, 16.1, 16.9, 17.9, 21.1, 22.7, 25.7, 26.6, 27.4, 27.9 +_ 0.2 degrees two theta. An X-ray diffractogram of a sample of Form I is attached as Figure 7. A typical thermogravimetric curve of Form I (Figure 8) shows a weight loss of about 10% over a range from room temperature to about 130°C.
U skladu s predmetnim izumom, predmetne nove forme ondansetron hidroklorida može se prirediti kao farmaceutske kompozicije koje su naročito korisne za liječenje niza različitih stanja, uključujući sprečavanje mučnine i povraćanja povezanog s nekim vrstama kemoterapije raka, radioterapijom i postoperativnom mučninom i/ili povraćanjem. Takve kompozicije obuhvaćaju jednu od novih formi ondansetron hidroklorida s farmaceutski prihvatljivim nosačima i/ili akscipijentima poznatima stručnjacima u području. In accordance with the present invention, the subject new forms of ondansetron hydrochloride can be prepared as pharmaceutical compositions that are particularly useful for the treatment of a number of different conditions, including the prevention of nausea and vomiting associated with some types of cancer chemotherapy, radiotherapy and postoperative nausea and/or vomiting. Such compositions include one of the new forms of ondansetron hydrochloride with pharmaceutically acceptable carriers and/or excipients known to those skilled in the art.
Preferirano, ove kompozicije se priređuju kao medikamenti za oralno ili intravenozno davanje. Prikladne forme za oralno davanje uključuju tablete, prešane ili presvučene pilule, dražeje, sašete, tvrde ili želatinske kapsule, tablete za pod jezik, sirupe i suspenzije. Dok će osoba uobičajenog znanja u struci razumjeti da će doziranje varirati u skladu s indikacijom, starosti pacijenta itd., općenito će se polimorfne i hidratne forme ondansetron hidroklorida predmetnog izuma davati u dnevnoj dozi od oko 8 do oko 32 mg na dan, i preferirano oko 8 do oko 24 mg na priložen i preferirano oko 8 do oko 24 mg na dan. Dodatno, nove forme ondansetron hidroklorida predmetnog izuma može se davati kao farmaceutska formulacija koja obuhvaća nove forme ondansetron hidroklorida u količini od oko 4 mg do oko 32 mg po tableti. Preferirano, nove forme ondansetron hidroklorida predmetnog izuma mogu se davati kao farmaceutska formulacija koja obuhvaća nove forme ondansetron hidroklorida u količini od 4 mg, 8 mg ili 24 mg po tableti. Dodatno, nove forme ondansetron hidroklorida predmetnog izuma mogu se davati kao oralna otopina koja obuhvaća nove forme ondansetron hidroklorida u količini od 4 mg ondansetrona u 5 ml. Preferably, these compositions are prepared as medicaments for oral or intravenous administration. Suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, sublingual tablets, syrups and suspensions. While one of ordinary skill in the art will understand that the dosage will vary according to the indication, age of the patient, etc., generally the polymorph and hydrate forms of ondansetron hydrochloride of the present invention will be administered at a daily dose of from about 8 to about 32 mg per day, and preferably about 8 to about 24 mg per attached and preferably about 8 to about 24 mg per day. Additionally, the novel forms of ondansetron hydrochloride of the present invention may be administered as a pharmaceutical formulation comprising the novel forms of ondansetron hydrochloride in an amount of from about 4 mg to about 32 mg per tablet. Preferably, the new forms of ondansetron hydrochloride of the present invention can be administered as a pharmaceutical formulation comprising the new forms of ondansetron hydrochloride in an amount of 4 mg, 8 mg or 24 mg per tablet. Additionally, the new forms of ondansetron hydrochloride of the present invention can be administered as an oral solution comprising the new forms of ondansetron hydrochloride in an amount of 4 mg of ondansetron in 5 ml.
PRIMJERI EXAMPLES
Rendgenski difraktogrami praškastog uzorka dobiveni su postupcima poznatima u struci primjenom Philips rengenskog difraktometra za prah Phillips Generator TW1830, Goniometer model POW3020, MPD Control POW3710, X-Ray cijev s Ću anodnom metom, Monochromator proporcionalni brojač, brzina snimanja 2° u minuti. X-ray diffractograms of the powder sample were obtained by methods known in the field using Philips X-ray powder diffractometer Phillips Generator TW1830, Goniometer model POW3020, MPD Control POW3710, X-Ray tube with Cu anode target, Monochromator proportional counter, recording speed 2° per minute.
Raspodjela veličine čestica dobivena je postupcima poznatima u struci laserskom difrakcijskom tehnikom; primjenom Malvern Laser Diffraction Mastersizer S, opremljenog ćelijom malog volumena od 50 - 80 ml kao protočnom ćelijom. Uzorci su dispergirani pomoću silicijske tekućine F-10 kao razrjeđivača i dodavanjem malog alikvota uzorka u 5 ml razrjeđivača unutar staklene boce od 10 ml. Suspenzija je miješana pomoću vira 5 sekundi i onda obrađivana ultrazvukom u otvorenoj boci 2 i pola minute da se razbiju tvrdi agregati. Suspenzija je dokapana u protočnu ćeliju ispunjenu razrjeđivačem dok nije postignuto potrebno zamućenje (15-28%) . Mjerenje je započeto nakon jedne minute kruženja na oko 1700 - 1800 rpm (okretaja u minuti) brzine pumpe. The particle size distribution was obtained by procedures known in the art using the laser diffraction technique; using the Malvern Laser Diffraction Mastersizer S, equipped with a small volume cell of 50 - 80 ml as a flow cell. Samples were dispersed using silica fluid F-10 as diluent and adding a small aliquot of the sample to 5 ml of diluent inside a 10 ml glass bottle. The suspension was vortexed for 5 seconds and then sonicated in an open bottle for 2.5 minutes to break up hard aggregates. The suspension was dripped into a flow cell filled with diluent until the required turbidity (15-28%) was achieved. The measurement was started after one minute of circulation at about 1700 - 1800 rpm (revolutions per minute) pump speed.
Kao što je poznato u struci, eksperimentalni uvjeti kao obrada ultrazvukom, vir ili bilo koji drugi disperzijski medij su namijenjene da dispergiraju čestice i razbiju agregate koji mogu biti prisutni u tvari kao rezultat lijepljenja čestica za vrijeme sušenja, na primjer, s namjerom da se dobije precizna raspodjela veličine čestica primarnih čestica. Stoga, primijenjeni eksperimentalni uvjeti mogu varirati prema izgledu uzoraka i prisutnosti agregata. As is known in the art, experimental conditions such as sonication, vortexing or any other dispersion medium are intended to disperse particles and break up aggregates that may be present in the substance as a result of particle sticking during drying, for example, with the intention of obtaining precise particle size distribution of primary particles. Therefore, the applied experimental conditions may vary according to the appearance of the samples and the presence of aggregates.
Preparacija ondansetron forme A s različitim razinama hidratacije iz ondansetron slobodne baze Preparation of ondansetron form A with different hydration levels from ondansetron free base
Primjer 1: Example 1:
Ondansetron baza (400 mg, 1.36 x 10-3 mol) suspendirana je u 40 ml apsolutnog etanola pri sobnoj temperaturi. Suspenzija je zagrijavana uz refluks da se ondansetron otopi. Nakon 20 min miješanja uz refluks dodana je etanolska otopina koja je sadržavala 1.1 ekvivalenata HCl. Reakcijska smjesa miješana je na ovoj temperaturi dodatnih 10 min i onda ohlađena polagano do 0°C. Ondansetron base (400 mg, 1.36 x 10-3 mol) was suspended in 40 ml of absolute ethanol at room temperature. The suspension was heated at reflux to dissolve the ondansetron. After 20 min of stirring under reflux, an ethanol solution containing 1.1 equivalents of HCl was added. The reaction mixture was stirred at this temperature for an additional 10 min and then cooled slowly to 0°C.
Nakon miješanja na 0°C 1 sat, krutina je filtrirana u vakuumu i osušena u vakuumu na 50°C da se dobije 90 mg ondansetron hidroklorid forme After stirring at 0°C for 1 hour, the solid was filtered under vacuum and dried under vacuum at 50°C to give 90 mg of ondansetron hydrochloride form
A. KF = 10% . A. KF = 10%.
Primjer 2: Example 2:
Ondansetron baza (400 mg, 1.36 x 10-3 mol) suspendirana je u 12 ml apsolutnog etanola pri sobnoj temperaturi. Suspenzija je zagrijavana uz refluks da se ondansetron otopi. Nakon 20 min miješanja uz refluks, dodana je etanolska otopina koja je sadržavala 1.1 ekvivalenata HCl. Reakcijska smjesa miješana je na ovoj temperaturi dodatnih 10 min i onda ohlađena polagano do 0°C. Nakon miješanja na 0°C 1 sat, krutina je filtrirana u vakuumu i osušena u vakuumu na 50°C da se dobije 536 mg ondansetron hidroklorid forme Ondansetron base (400 mg, 1.36 x 10-3 mol) was suspended in 12 ml of absolute ethanol at room temperature. The suspension was heated at reflux to dissolve the ondansetron. After 20 min of stirring under reflux, an ethanol solution containing 1.1 equivalents of HCl was added. The reaction mixture was stirred at this temperature for an additional 10 min and then cooled slowly to 0°C. After stirring at 0°C for 1 hour, the solid was vacuum filtered and dried in vacuo at 50°C to give 536 mg of ondansetron hydrochloride form
A. KF = 8.1%. A. KF = 8.1%.
Primjer 3: Example 3:
Ondansetron baza (400 mg, 1.36 x 10-3 mol) suspendirana je u 16 ml smjese l : l etanola i izopropanola pri sobnoj temperaturi. Suspenzija je zagrijavana uz refluks da se ondansetron otopi. Nakon 20 min miješanja uz refluks dodana je etanolska otopina koja je sadržavala 1.1 ekvivalenata HCl. Reakcijska smjesa miješana je na ovoj temperaturi dodatnih 10 min. Uparavanje otapala dalo je ondansetron hidroklorid dihidrat formu A. Ondansetron base (400 mg, 1.36 x 10-3 mol) was suspended in 16 ml of a mixture of 1:1 ethanol and isopropanol at room temperature. The suspension was heated at reflux to dissolve the ondansetron. After 20 min of stirring under reflux, an ethanol solution containing 1.1 equivalents of HCl was added. The reaction mixture was stirred at this temperature for an additional 10 min. Evaporation of the solvent gave ondansetron hydrochloride dihydrate form A.
Primjer 4: Example 4:
Ondansetron baza (400 mg, 1.36 x 10-3 mol) suspendirana je u 40 ml apsolutnog etanola pri sobnoj temperaturi. Suspenzija je zagrijavana uz refluks da se ondansetron otopi. Nakon 20 min miješanja uz refluks dodana je etanolska otopina koja je sadržavala 1.1 ekvivalenata HCl. Reakcijska smjesa miješana je na ovoj temperaturi dodatnih 10 min i onda ohlađena polagano do 0°C. Nakon miješanja na 0°C 1 sat, krutina je filtrirana u vakuumu i osušena u vakuumu na 50°C da se dobije 320 mg ondansetron hidroklorid forma A. Ondansetron base (400 mg, 1.36 x 10-3 mol) was suspended in 40 ml of absolute ethanol at room temperature. The suspension was heated at reflux to dissolve the ondansetron. After 20 min of stirring under reflux, an ethanol solution containing 1.1 equivalents of HCl was added. The reaction mixture was stirred at this temperature for an additional 10 min and then cooled slowly to 0°C. After stirring at 0°C for 1 hour, the solid was filtered in vacuo and dried in vacuo at 50°C to give 320 mg of ondansetron hydrochloride Form A.
KF = 8.1%. KF = 8.1%.
Primjer 5: Example 5:
Ondansetron baza (400 mg, 1.36 x 10-3 mol) suspendirana je u 14 ml apsolutnog etanola pri sobnoj temperaturi. Suspenzija je zagrijavana uz refluks da se ondansetron otopi. Nakon 20 min miješanja uz refluks dodana je etanolska otopina koja je sadržavala 1.5 ekvivalenata HCl. Reakcijska smjesa miješana je na ovoj temperaturi dodatnih 10 min. Uparavanje otapala dalo je 280 mg ondansetron hidroklorid forme A. Ondansetron base (400 mg, 1.36 x 10-3 mol) was suspended in 14 ml of absolute ethanol at room temperature. The suspension was heated at reflux to dissolve the ondansetron. After 20 min of stirring under reflux, an ethanol solution containing 1.5 equivalents of HCl was added. The reaction mixture was stirred at this temperature for an additional 10 min. Evaporation of the solvent gave 280 mg of ondansetron hydrochloride Form A.
KF = 9.3%. KF = 9.3%.
Primjer 6: Example 6:
Ondansetron baza (400 mg, 1.36 x 10-3 mol) suspendirana je u 12 ml apsolutnog etanola pri sobnoj temperaturi. Molekulska sita veličine četiri angstroma dodana su u tikvicu. Suspenzija je onda zagrijavana uz refluks da se ondansetron otopi. Nakon 20 min miješanja uz refluks dodana je etanolska otopina koja je sadržavala 1.5 ekvivalenata HCl. Reakcijska smjesa miješana je na ovoj temperaturi dodatnih 10 min i onda ohlađena polagano do 0°C. Nakon miješanja na 0°C 1 sat, krutina je filtrirana u vakuumu i osušena u vakuumu na 50°C da se dobije 296 mg of ondansetron hidroklorid forma A. Ondansetron base (400 mg, 1.36 x 10-3 mol) was suspended in 12 ml of absolute ethanol at room temperature. Four angstrom molecular sieves were added to the flask. The suspension was then heated at reflux to dissolve the ondansetron. After 20 min of stirring under reflux, an ethanol solution containing 1.5 equivalents of HCl was added. The reaction mixture was stirred at this temperature for an additional 10 min and then cooled slowly to 0°C. After stirring at 0°C for 1 hour, the solid was filtered under vacuum and dried under vacuum at 50°C to give 296 mg of ondansetron hydrochloride form A.
KF = 9.5%. KF = 9.5%.
Primjer 7: Example 7:
Ondansetron baza (400 mg, 1.36 x 10-3 mol) suspendirana je u 20 ml apsolutnog etanola pri sobnoj temperaturi. Suspenzija je zagrijavana uz refluks da se ondansetron otopi. Nakon 20 min miješanja uz refluks dodana je otopina koja je sadržavala 1.1 ekvivalenata HCl u izopropanolu. Reakcijska smjesa miješana je na ovoj temperaturi dodatnih 10 min i onda ohlađena polagano do 0°C. Nakon miješanja na 0°C 1 sat krutina je filtrirana u vakuumu i osušena u vakuumu na 50°C da se dobije 290 mg ondansetron hidroklorid forme A. Ondansetron base (400 mg, 1.36 x 10-3 mol) was suspended in 20 ml of absolute ethanol at room temperature. The suspension was heated at reflux to dissolve the ondansetron. After 20 min of stirring under reflux, a solution containing 1.1 equivalents of HCl in isopropanol was added. The reaction mixture was stirred at this temperature for an additional 10 min and then cooled slowly to 0°C. After stirring at 0°C for 1 hour, the solid was vacuum filtered and dried in vacuo at 50°C to give 290 mg of ondansetron hydrochloride form A.
KF = 9.5%. KF = 9.5%.
Primjer 8: Example 8:
Ondansetron baza (2.5 g, 8.5 x 10-3 mol) otopljena je u 80 ml kloroforma pri sobnoj temperaturi. Onda je propuštano 1.1 ekv. plinovitog HCl kroz otopinu kroz 20 min. Reakcijska smjesa miješana je na pri sobnoj temperaturi dodatnih 30 min. Krutina je filtrirana u vakuumu i osušena u vakuumu na 50°C da se dobije 2.8 g ondansetron hidroklorid forme A. KF = 5.4%. Ondansetron base (2.5 g, 8.5 x 10-3 mol) was dissolved in 80 ml of chloroform at room temperature. Then 1.1 equiv was passed through. of gaseous HCl through the solution for 20 min. The reaction mixture was stirred at room temperature for an additional 30 min. The solid was filtered in vacuo and dried in vacuo at 50°C to give 2.8 g of ondansetron hydrochloride form A. KF = 5.4%.
Primjer 9: Example 9:
Ondansetron baza (2.5 g, 8.5 x 10-3 mol) otopljena je u 87.5 ml kloroforma pri sobnoj temperaturi. Onda je propuštano 1.1 ekv. plinovitog HCl kroz otopinu kroz 20 min. Reakcijska smjesa miješana je na pri sobnoj temperaturi dodatnih 30 min. Krutina je filtrirana u vakuumu i osušena u vakuumu na 50°C da se dobije 2.5 g ondansetron hidroklorid forme A. Ondansetron base (2.5 g, 8.5 x 10-3 mol) was dissolved in 87.5 ml of chloroform at room temperature. Then 1.1 equiv was passed through. of gaseous HCl through the solution for 20 min. The reaction mixture was stirred at room temperature for an additional 30 min. The solid was filtered in vacuo and dried in vacuo at 50°C to give 2.5 g of ondansetron hydrochloride form A.
Primjer 10: Example 10:
Ondansetron baza g (5 g, 17.06 x 10-3 mol) otopljena je u 175 ml kloroforma pri sobnoj temperaturi. Onda je propuštan plinoviti HCl pri sobnoj temperaturi 15 min. Polagano je dodano 0.6 ekvivalenata HaO u reakcijsku smjesu. Reakcijska smjesa je miješana pri sobnoj temperaturi dodatna 3 sata. Onda je krutina filtrirana u vakuumu i osušena u vakuumu na 50°C da se dobije 6.3 g ondansetron hidroklorid forme A. Ondansetron base g (5 g, 17.06 x 10-3 mol) was dissolved in 175 ml of chloroform at room temperature. Gaseous HCl was then passed through at room temperature for 15 min. 0.6 equivalents of HaO was slowly added to the reaction mixture. The reaction mixture was stirred at room temperature for an additional 3 hours. The solid was then filtered under vacuum and dried under vacuum at 50°C to give 6.3 g of ondansetron hydrochloride form A.
KF = 8.4%. KF = 8.4%.
Primjer 11: Example 11:
Ondansetron baza g (5 g, 17.06 x 10-3 mol) je suspendirana u smjesi H2O/CHCl3 (140/20 v/v) pri sobnoj temperaturi. Reakcijska smjesa je zagrijana do temperature refluksa i onda je dodano 1.1 ekv. l N vodene otopine HCl upumpavanjem pri 1 ml/min. Reakcijska smjesa je miješana pri sobnoj temperaturi 30 min i onda polagano ohlađena na 5°C. Talog nastao djelomičnim taloženjem za vrijeme hlađenja je filtriran (1.7g) u vakuumu i osušen u vakuumu na 50°C da se dobije bijela krutina. Matičnica je ostavljena preko noći pri sobnoj temperaturi da se dobije dodatni talog (1.7 g) koji je filtriran i osušen u vakuumu. Obje frakcije dale su ondansetron hidroklorid formu A. Ondansetron base g (5 g, 17.06 x 10-3 mol) was suspended in a mixture of H2O/CHCl3 (140/20 v/v) at room temperature. The reaction mixture was heated to reflux and then 1.1 eq. was added. l N aqueous solution of HCl by pumping at 1 ml/min. The reaction mixture was stirred at room temperature for 30 min and then slowly cooled to 5°C. The precipitate formed by partial precipitation during cooling was filtered (1.7g) in vacuo and dried in vacuo at 50°C to give a white solid. The mother liquor was left overnight at room temperature to obtain an additional precipitate (1.7 g) which was filtered and dried under vacuum. Both fractions yielded ondansetron hydrochloride form A.
Preparacija ondansetron forma A monohidrata iz ondansetron hidroklorid forma A dihidrata Preparation of ondansetron form A monohydrate from ondansetron hydrochloride form A dihydrate
Primjer 12: Example 12:
Ondansetron hidroklorid forma A dihidrat (5 g) u 70 ml 96% vodene otopine EtOH zagrijavan je uz temperaturu refluksa 22 sata. Reakcijska smjesa je onda puštena da se ohladi do sobne temperature i onda ohlađena na 0°C. Krutina koja je istaložena filtrirana je i sušena na 65°C 20 sati čime se dobilo 1.2 g ondansetron hidroklorid forma A monohidrata. Ondansetron hydrochloride form A dihydrate (5 g) in 70 ml of 96% aqueous EtOH was heated at reflux for 22 hours. The reaction mixture was then allowed to cool to room temperature and then cooled to 0°C. The precipitated solid was filtered and dried at 65°C for 20 hours to give 1.2 g of ondansetron hydrochloride form A monohydrate.
KF = 5.4%. KF = 5.4%.
Primjer 13: Example 13:
Ondansetron hidroklorid forma A dihidrat (5 g) u 70 ml 96% vodene otopine EtOH zagrijavan je uz temperaturu refluksa 22 sata. Reakcijska smjesa je onda puštena da se ohladi do sobne temperature i onda ohlađena na 0°C. Krutina je onda filtrirana, sušena na 65°C 20 sati da se dobije 4.0 g ondansetron hidroklorid forma A monohidrat. Ondansetron hydrochloride form A dihydrate (5 g) in 70 ml of 96% aqueous EtOH was heated at reflux for 22 hours. The reaction mixture was then allowed to cool to room temperature and then cooled to 0°C. The solid was then filtered, dried at 65°C for 20 hours to give 4.0 g of ondansetron hydrochloride form A monohydrate.
KF = 5.0%. KF = 5.0%.
Primjer 14: Example 14:
Ondansetron hidroklorid forma A dihidrat (5.0 g) razmuljivan je u 70 ml 90% vodene otopine EtOH pri sobnoj temperaturi 22 sata. Krutina je onda filtrirana, sušena na 65°C 20 sati da se dobije 3.5 g ondansetron hidroklorid forma A monohidrat. Ondansetron hydrochloride form A dihydrate (5.0 g) was slurried in 70 ml of 90% aqueous EtOH solution at room temperature for 22 hours. The solid was then filtered, dried at 65°C for 20 hours to give 3.5 g of ondansetron hydrochloride form A monohydrate.
KF = 5.2%. KF = 5.2%.
Primjer 15: Example 15:
Ondansetron hidroklorid forma A dihidrat (5.0 g) razmuljivan je u 70 ml 50% vodene otopine EtOH pri sobnoj temperaturi 22 sata. Onda je dodan metil etil keton (100 ml) da se istaloži ondansetron hidroklorid. Smjesa je ohlađena na 0°C i talog je filtriran je i sušen na 65°C 20 sati da se dobije 0.4 g ondansetron hidroklorid forma A monohidrata. Ondansetron hydrochloride form A dihydrate (5.0 g) was slurried in 70 ml of 50% aqueous EtOH solution at room temperature for 22 hours. Methyl ethyl ketone (100 ml) was then added to precipitate the ondansetron hydrochloride. The mixture was cooled to 0°C and the precipitate was filtered and dried at 65°C for 20 hours to give 0.4 g of ondansetron hydrochloride form A monohydrate.
KF = 5.2%. KF = 5.2%.
Primjer 16: Example 16:
Ondansetron hidroklorid forma A dihidrat (5.0 g) razmuljivan je u 70 ml 50% vodene otopine EtOH pri sobnoj temperaturi 22 sata. Krutina je onda filtrirana, sušena na 65°C 20 sati da se dobije 0.4 g ondansetron hidroklorid forma A monohidrat. Ondansetron hydrochloride form A dihydrate (5.0 g) was slurried in 70 ml of 50% aqueous EtOH solution at room temperature for 22 hours. The solid was then filtered, dried at 65°C for 20 hours to give 0.4 g of ondansetron hydrochloride form A monohydrate.
KF = 5.7%. KF = 5.7%.
Nešto spoja dobiveno je iz matičnice dodavanjem 125 ml MEK za taloženje i filtriranje u vakuumu. Krutina je sušena na 65°C 20 sati da se dobije 1.7 g ondansetron hidroklorid forma A monohidrat. Some of the compound was recovered from the mother plant by adding 125 ml of MEK for precipitation and vacuum filtration. The solid was dried at 65°C for 20 hours to give 1.7 g of ondansetron hydrochloride form A monohydrate.
KF = 5.4%. KF = 5.4%.
Primjer 17: Example 17:
Ondansetron hidroklorid forma A dihidrat (5.0 g) razmuljivan je u 70 ml 96% vodene otopine EtOH pri sobnoj temperaturi 22 sata. Krutina je onda filtrirana, sušena na 65°C 20 sati da se dobije 3.8 g ondansetron hidroklorid forma A. Ondansetron hydrochloride form A dihydrate (5.0 g) was slurried in 70 ml of 96% aqueous EtOH solution at room temperature for 22 hours. The solid was then filtered, dried at 65°C for 20 hours to give 3.8 g of ondansetron hydrochloride form A.
KF = 6.1% KF = 6.1%
Primjer 18: Example 18:
Muljevita smjesa 5 g ondansetron hidroklorid forma A dihidrata u smjesi EtOH/IPA (40ml/65 ml) obrađivana je ultrazvukom 2 min, amplituda 50%, energija 3.5 KJ. Onda je bijela krutina filtrirana pomoću 8 mm filter papira i sušena na 65°C 20 sati da se dobije 2.7 g ondansetron hidroklorid forma A. A slurry mixture of 5 g of ondansetron hydrochloride form A dihydrate in EtOH/IPA mixture (40 ml/65 ml) was treated with ultrasound for 2 min, amplitude 50%, energy 3.5 KJ. Then the white solid was filtered using 8 mm filter paper and dried at 65°C for 20 hours to obtain 2.7 g of ondansetron hydrochloride form A.
KF = 4.8%. KF = 4.8%.
Primjer 19: Example 19:
Tikvica od 250 ml napunjena je suspenzijom ondansetron hidroklorid forma A dihidrata (5 g) u smjesi EtOH/toluen (110 ml/50 ml). Tikvica je opremljena aparaturom za destilaciju. Oddestilirano je četrdeset pet mililitara otapala pri atmosferskom tlaku dok nije dobivena bistra otopina. Reakcijska smjesa je onda puštena da se hladi na 10°C 1 sat. Talog je filtriran u vakuumu i sušen u vakuumskoj peći na 50°C 16 sati da se dobije 3.7 g ondansetron hidroklorid forma A. A 250 ml flask was filled with a suspension of ondansetron hydrochloride form A dihydrate (5 g) in EtOH/toluene (110 ml/50 ml). The flask is equipped with a distillation apparatus. Forty-five milliliters of solvent were distilled off at atmospheric pressure until a clear solution was obtained. The reaction mixture was then allowed to cool to 10°C for 1 hour. The precipitate was vacuum filtered and dried in a vacuum oven at 50°C for 16 hours to give 3.7 g of ondansetron hydrochloride form A.
KF = 6.1 %. KF = 6.1 %.
Preparacija ondansetron hidroklorid forme A sa sadržajem vode između 6 i 9 posto Preparation of ondansetron hydrochloride form A with a water content between 6 and 9 percent
Primjer 20: Example 20:
Muljevita smjesa 5 g ondansetron hidroklorid forma A dihidrata u 90% vodenoj otopini EtOH (70 ml) obrađivana je ultrazvukom 2 minute s amplitudom 50%, i energijom 3.5 kJ. Onda je bijela krutina filtrirana pomoću 8 mm filter papira i sušena na 65°C 20 sati da se dobije 2.7 g ondansetron hidroklorid forme A. A slurry mixture of 5 g of ondansetron hydrochloride form A dihydrate in 90% aqueous EtOH solution (70 ml) was sonicated for 2 minutes with an amplitude of 50% and an energy of 3.5 kJ. Then the white solid was filtered using 8 mm filter paper and dried at 65°C for 20 hours to obtain 2.7 g of ondansetron hydrochloride form A.
KF = 6.6%. KF = 6.6%.
Primjer 21: Example 21:
Muljevita smjesa 5 g ondansetron hidroklorid forma A dihidrata u smjesi EtOH/IPA (65 ml/40 ml) obrađivana je ultrazvukom 2 min., amplituda 50%, energija 3.5 kJ. Onda je-bijela krutina filtrirana pomoću 8 mm filter papira i sušena na 65°C 20 sati da se dobije 3.6 g ondansetron hidroklorid forma A. A slurry mixture of 5 g of ondansetron hydrochloride form A dihydrate in EtOH/IPA mixture (65 ml/40 ml) was treated with ultrasound for 2 min., amplitude 50%, energy 3.5 kJ. Then the off-white solid was filtered using 8 mm filter paper and dried at 65°C for 20 hours to obtain 3.6 g of ondansetron hydrochloride form A.
KF = 6.7% KF = 6.7%
Primjer 22: Example 22:
Muljevita smjesa 5 g ondansetron hidroklorid forma A dihidrata u toluenu (100 ml) zagrijavana je na 100°C 17 sati. Reakcijska smjesa je onda ohlađena na 0 °C. Bijela krutina filtrirana je u vakuumu i sušena u vakuumskoj peći na 50°C 16 sati da se dobije 4.0 g ondansetron hidroklorid forma A. A slurry of 5 g of ondansetron hydrochloride form A dihydrate in toluene (100 ml) was heated at 100°C for 17 hours. The reaction mixture was then cooled to 0 °C. The white solid was vacuum filtered and dried in a vacuum oven at 50°C for 16 hours to give 4.0 g of ondansetron hydrochloride form A.
KF = 7.8%. KF = 7.8%.
Primjer 23: Example 23:
Ondansetron hidroklorid forma A dihidrat (5 g) u smjesi apsolutni EtOH/toluen (45 ml/20 ml) zagrijavan je do temperature refluksa nekoliko sati. Nakon miješanja pri sobnoj temperaturi preko noći, krutina je filtrirana u vakuumu i sušena u vakuumskoj peći na 50°C 16 sati da se dobije 4.0 g ondansetron hidroklorid forma A. Ondansetron hydrochloride form A dihydrate (5 g) in absolute EtOH/toluene (45 ml/20 ml) was heated to reflux temperature for several hours. After stirring at room temperature overnight, the solid was vacuum filtered and dried in a vacuum oven at 50°C for 16 hours to give 4.0 g of ondansetron hydrochloride form A.
KF = 7.8%. KF = 7.8%.
Primjer 24: Example 24:
Ondansetron hidroklorid dihidrat forma a. (2.1 g) u smjesi EtOH/toluene (45 ml/20 ml) zagrijavana je do temperature refluksa. Onda je oddestilirano 25 ml mililitara otapala pri atmosferskom tlaku. Reakcijska smjesa je onda puštena da se hladi na 10°C 3 sata. Bijeli talog je filtriran u vakuumu i sušen u vakuumskoj peći na 50°C 5 sati da se dobije 1.4 g ondansetron hidroklorid forma A. Ondansetron hydrochloride dihydrate form a. (2.1 g) in a mixture of EtOH/toluene (45 ml/20 ml) was heated to reflux temperature. Then 25 ml milliliters of solvent were distilled off at atmospheric pressure. The reaction mixture was then allowed to cool to 10°C for 3 hours. The white precipitate was vacuum filtered and dried in a vacuum oven at 50°C for 5 hours to give 1.4 g of ondansetron hydrochloride form A.
KF = 8.8% KF = 8.8%
Primjer 25: Example 25:
Muljevita smjesa 5 g ondansetron hidroklorid forma A dihidrata u apsolutnom EtOH (70 ml) obrađivana je ultrazvukom 2 minute s amplitudom 50% i energijom 3.5 kJ. Onda je bijela krutina filtrirana pomoću 3 mm filter papira i sušena na 65°C 20 sati da se dobije 3.3 g ondansetron hidroklorid forma A. A slurry of 5 g of ondansetron hydrochloride form A dihydrate in absolute EtOH (70 ml) was sonicated for 2 minutes with an amplitude of 50% and an energy of 3.5 kJ. Then the white solid was filtered using 3 mm filter paper and dried at 65°C for 20 hours to obtain 3.3 g of ondansetron hydrochloride form A.
KF = 9.3% KF = 9.3%
Preparacija bezvodne ondansetron hidroklorid forme B Preparation of anhydrous ondansetron hydrochloride form B
Primjer 26: Example 26:
U tikvicu opremljenu cjevčicom za sušenje sa CaCl2 dodano je 5.0 g ondansetron HCl forme A i smjesa IPA/EtOH (40/65 ml). Smjesa je miješana pri sobnoj temperaturi 22 sata. Nakon filtriranja dobivena krutina je sušena na 65°C 20 sati da se dobije 4.0 g bezvodne ondansetron hidroklorid forme B. 5.0 g of ondansetron HCl form A and a mixture of IPA/EtOH (40/65 ml) were added to a flask equipped with a drying tube with CaCl2. The mixture was stirred at room temperature for 22 hours. After filtration, the resulting solid was dried at 65°C for 20 hours to obtain 4.0 g of anhydrous ondansetron hydrochloride form B.
KF = 0.6%. KF = 0.6%.
Primjer 27: Example 27:
U tikvicu opremljenu cjevčicom za sušenje sa CaCl2 dodano je 5.0 g ondansetron HCl forme A i apsolutni EtOH (70 ml). Smjesa je miješana pri sobnoj temperaturi 22 sati. Nakon filtriranja dobivena krutina je sušena na 65°C 20 sati da se dobije 3.7 g ondansetron forma B, HCl. 5.0 g of ondansetron HCl form A and absolute EtOH (70 ml) were added to a flask equipped with a drying tube with CaCl2. The mixture was stirred at room temperature for 22 hours. After filtration, the resulting solid was dried at 65°C for 20 hours to obtain 3.7 g of ondansetron form B, HCl.
KF = 0.4%. KF = 0.4%.
Primjer 28: Example 28:
U tikvicu s tri grla opremljenu hladilom, temometrom i CaCl2 cjevčicom dodana je ondansetron baza (2.0 g) i 280 ml toluena. Smjesa je zagrijavana uz refluks dok nije dobivena bistra otopina. HCl je propuštan dok nije postignut pH 1. Reakcijska smjesa je zagrijavana uz refluks dodatni 1 sat, onda ohlađena do sobne temperature. Dobiveni talog je filtriran je i sušen na 65°C 20 sati da se dobije 1.7 g ondansetron forma B HCl. Ondansetron base (2.0 g) and 280 ml of toluene were added to a three-necked flask equipped with a condenser, a thermometer, and a CaCl2 tube. The mixture was heated under reflux until a clear solution was obtained. HCl was passed through until pH 1 was reached. The reaction mixture was heated at reflux for an additional 1 hour, then cooled to room temperature. The resulting precipitate was filtered and dried at 65°C for 20 hours to obtain 1.7 g of ondansetron form B HCl.
KF = 1.6%. KF = 1.6%.
Primjer 29: Example 29:
Ondansetron baza (2.0 g, 6.8 x 10-3 mol) je suspendirana u MEK (220 ml) 30 minuta dok nije došlo do potpunog otapanja. Onda je propuštan plinoviti HCl dok otopina nije postigla pH = 1. Reakcijska smjesa je zagrijavana uz refluks dodatni 1 sat, ohlađena do sobne temperature, filtrirana u vakuumu i sušena na 65°C 20 sati. Dobivena bijela krutina razmuljivana je u apsolutnom etanolu (70 ml) pri sobnoj temperaturi 22 sata korištenjem CaCl2 cjevčice. Reakcijska smjesa je onda filtrirana u vakuumu i sušena na 65°C 20 sati da se dobije 1.9 g bezvodne ondansetron hidroklorid forme B. Ondansetron base (2.0 g, 6.8 x 10-3 mol) was suspended in MEK (220 ml) for 30 minutes until complete dissolution occurred. Then gaseous HCl was passed until the solution reached pH = 1. The reaction mixture was heated under reflux for an additional 1 hour, cooled to room temperature, filtered under vacuum and dried at 65°C for 20 hours. The resulting white solid was slurried in absolute ethanol (70 ml) at room temperature for 22 hours using a CaCl2 tube. The reaction mixture was then vacuum filtered and dried at 65°C for 20 hours to give 1.9 g of anhydrous ondansetron hydrochloride form B.
Primjer 30: Example 30:
Ondansetron baza (3 g) (10. x 2 10-3 mol) je suspendirana u MEK (330 ml) 15 minuta dok nije došlo do potpunog otapanja. Onda je dodana etanolska otopina HCl (1.5 ekv). Reakcijska smjesa je zagrijavana uz refluks dodatnih 30 minuta, ohlađena do sobne temperature, filtrirana u vakuumu i sušena na 65°C 20 sati. Dobivena bijela krutina razmuljivana je u 105 ml smjese EtOH aps/IPA (65/40 ml) pri sobnoj temperaturi 22 sata korištenjem CaCl2 cjevčice. Reakcijska smjesa je onda filtrirana u vakuumu i sušena na 65°C 20 sati da se dobije 3.16 g bezvodne ondansetron hidroklorid forme B. Ondansetron base (3 g) (10 x 2 10-3 mol) was suspended in MEK (330 ml) for 15 minutes until complete dissolution. Then an ethanolic solution of HCl (1.5 eq) was added. The reaction mixture was heated under reflux for an additional 30 minutes, cooled to room temperature, filtered under vacuum and dried at 65°C for 20 hours. The obtained white solid was slurried in 105 ml of a mixture of EtOH aps/IPA (65/40 ml) at room temperature for 22 hours using a CaCl2 tube. The reaction mixture was then vacuum filtered and dried at 65°C for 20 hours to give 3.16 g of anhydrous ondansetron hydrochloride form B.
Primjer 31: Example 31:
Ondansetron baza (5 g) (17.0 x 10-3 mol) je suspendirana u 250 ml apsolutnog etanola, EtOH. Onda je dodana etanolska otopina HCl (1.5 ekv). Reakcijska smjesa je zagrijavana (45°C) da se dobije bistra otopina. Reakcijska smjesa je puštena da se ohladi do sobne temperature i onda je dodan suhi eter (430 ml) kako bi se istaložila krutina. Talog je filtriran u vakuumu i sušen u vakuumskoj peći na 65°C 24 sata da se dobije 3.16 g bezvodne ondansetron hidroklorid forme. Ondansetron base (5 g) (17.0 x 10-3 mol) was suspended in 250 ml of absolute ethanol, EtOH. Then an ethanolic solution of HCl (1.5 eq) was added. The reaction mixture was heated (45°C) to give a clear solution. The reaction mixture was allowed to cool to room temperature and then dry ether (430 mL) was added to precipitate the solid. The precipitate was vacuum filtered and dried in a vacuum oven at 65°C for 24 hours to give 3.16 g of the anhydrous ondansetron hydrochloride form.
KF = 1.0%. KF = 1.0%.
Primjer 32: Example 32:
Ondansetron baza (5 g) (17.0 x 10-3 mol) je suspendirana u 250 ml apsolutnog etanola, EtOH. Onda ja dodana etanolska otopina HCl (1.5 ekv). Etanolska otopina je priređena propuštanjem plinovitog HCl u apsolutni etanol u suhim uvjetima. Reakcijska smjesa je zagrijavana (45°C) da se dobije bistra otopina i provedeno je vruće filtriranje bistre otopine. Ovom filtratu je dodan, pri sobnoj temperaturi, suhi eter (430 ml) da se istaloži krutina. Talog je filtriran u vakuumu i sušen u peći 65°C 18 sati da se dobije 3.16 g bezvodna ondansetron hidroklorid forma B. Ondansetron base (5 g) (17.0 x 10-3 mol) was suspended in 250 ml of absolute ethanol, EtOH. Then I added an ethanol solution of HCl (1.5 eq). The ethanol solution was prepared by passing gaseous HCl into absolute ethanol under dry conditions. The reaction mixture was heated (45°C) to give a clear solution and hot filtration of the clear solution was performed. To this filtrate was added, at room temperature, dry ether (430 ml) to precipitate the solid. The precipitate was filtered in vacuo and dried in an oven at 65°C for 18 hours to give 3.16 g of anhydrous ondansetron hydrochloride form B.
KF = 1.0 % KF = 1.0 %
Preparacija ondansetron hidroklorid forme C Preparation of ondansetron hydrochloride form C
Primjer 33: Example 33:
Ondansetron baza (1.5 g, 5.11 x 10-3 mol) je otopljena u apsolutnom etanolu (150 ml) svježe destiliranom pri temperaturi refluksa. Onda je dodana etanolska otopina HCl (1.1 ekv) uz refluks. Smjesa je miješana 20 minuta i puštena da se polagano ohladi do sobne temperature. Pojavio se vrlo gusti talog pri sobnoj temperaturi. Smjesa je onda filtrirana u vakuumu da se dobije 536 mg bijele krutine. Etanolska faza je uparena pod sniženim pritiskom da se dobije 824 mg Ondansetron hidroklorid forme C. Ondansetron base (1.5 g, 5.11 x 10-3 mol) was dissolved in absolute ethanol (150 ml) freshly distilled at reflux temperature. Then an ethanolic solution of HCl (1.1 eq) was added under reflux. The mixture was stirred for 20 minutes and allowed to cool slowly to room temperature. A very thick precipitate appeared at room temperature. The mixture was then filtered in vacuo to give 536 mg of a white solid. The ethanol phase was evaporated under reduced pressure to give 824 mg of Ondansetron hydrochloride Form C.
KF = 9.9% KF = 9.9%
Primjer 34: Example 34:
Ondansetron baza (5 g) (17.0 x 10-3 mol) je suspendirana u apsolutnom etanolu (150 ml) svježe destiliranom s 10 g 4A molekulskih sita. Reakcijska smjesa je zagrijana do 80 -°C do potpunog otapanja polazne tvari. Onda je dokapana etanolska otopina HCl (1.5 ekv) kod ove temperature i reakcijska smjesa je miješana 15 minuta. Smjesa je puštena da se polagano ohladi do sobne temperature i onda do 0°C da se dovrši taloženje. Smjesa s krutinom je onda filtrirana u vakuumu, isprana 3 puta sIPA (3 x 10 ml) da se dobije 3.07 g bijele krutine. Etanolska faza je puštena na 4°C preko noći i onda je talog filtriran pod sniženim tlakom da se dobije 600 mg krutine. Matičnica ove frakcije je onda uparena pod sniženim tlakom da se dobije 1 g Ondansetron hidroklorid forme C. Ondansetron base (5 g) (17.0 x 10-3 mol) was suspended in absolute ethanol (150 ml) freshly distilled with 10 g of 4A molecular sieves. The reaction mixture was heated to 80 -°C until complete dissolution of the starting material. Then ethanolic solution of HCl (1.5 eq) was added dropwise at this temperature and the reaction mixture was stirred for 15 minutes. The mixture was allowed to cool slowly to room temperature and then to 0°C to complete precipitation. The solid mixture was then vacuum filtered, washed 3 times with sIPA (3 x 10 ml) to give 3.07 g of a white solid. The ethanol phase was left at 4°C overnight and then the precipitate was filtered under reduced pressure to give 600 mg of solid. The mother liquor of this fraction was then evaporated under reduced pressure to give 1 g of Ondansetron hydrochloride Form C.
KF = 9.9% KF = 9.9%
Preparacija ondansetron hidroklorid forme D Preparation of ondansetron hydrochloride form D
Primjer 35: Example 35:
Ondansetron hidroklorid forma A je suspendirana (5 g) (17.0 x IO"3 mol) u ksilenu (5 ml). Suspenzija je zagrijana iznad 180°C da se ondansetron hidroklorid rastali. Onda je talina ulivena polagano u otopinu apsolutnog EtOH (50 ml) pri -10°C. Nastala krutina je miješana u apsolutnom EtOH 30 minuta na -10°C i onda gravitacijski filtrirana. Krutina je sušena u peći na 65°C 18 sati da se dobije 1.31 g ondansetron hidroklorid forme D. KF = 3.84% Ondansetron hydrochloride Form A was suspended (5 g) (17.0 x 10"3 mol) in xylene (5 ml). The suspension was heated above 180°C to dissolve the ondansetron hydrochloride. Then the melt was poured slowly into a solution of absolute EtOH (50 ml ) at -10° C. The resulting solid was stirred in absolute EtOH for 30 minutes at -10° C and then gravity filtered. The solid was dried in an oven at 65° C for 18 hours to give 1.31 g of ondansetron hydrochloride form D. KF = 3.84 %
Preparacija ondansetron hidroklorid forme E Preparation of ondansetron hydrochloride form E
Primjer 36: Example 36:
Ondansetron hidroklorid forma A (5 g, 13.6 x 10-3mol) razmuljivana je u IPA (70 ml) pri sobnoj temperaturi preko noći. Bijela krutina je onda filtrirana u vakuumu i sušena u peći na 65°C 24 sata da se dobije 4.9 g ondansetron hidroklorid forme E kao bijela krutina. Ondansetron hydrochloride form A (5 g, 13.6 x 10-3 mol) was slurried in IPA (70 ml) at room temperature overnight. The white solid was then filtered in vacuo and dried in an oven at 65°C for 24 hours to give 4.9 g of ondansetron hydrochloride Form E as a white solid.
KF = 1.8%. KF = 1.8%.
Primjer 37: Example 37:
Ondansetron hidroklorid forma A (5 g, 13.6 x 10-3mol) razmuljivana je u IPA (40 ml) na temperaturi refluks preko noći. Bijela krutina je filtrirana u vakuumu i sušena u peći na 65°C 24 sata da se dobije 5 g ondansetron hidroklorid forme E kao bijela krutina. Ondansetron hydrochloride form A (5 g, 13.6 x 10-3 mol) was slurried in IPA (40 ml) at reflux temperature overnight. The white solid was filtered in vacuo and dried in an oven at 65°C for 24 hours to give 5 g of ondansetron hydrochloride Form E as a white solid.
KF = 2.1 %. KF = 2.1 %.
Preparacija ondansetron hidroklorid forme H Preparation of ondansetron hydrochloride form H
Primjer 38: Example 38:
Ondansetron baza (5 g) (17.0 x 10-3 mol) je suspendirana u 250 ml apsolutnog etanola, EtOH. Onda je dodana etanolska otopina HCl (1.5 ekv). Reakcijska smjesa je zagrijavana (45°C) dok nije dobivena bistra otopina i provedeno je vruće filtriranje bistre otopine. Ovom filtratu je dodan terc-butil metil eter (200 ml) da se obori krutina. Onda je talog filtriran u vakuumu i sušen u peći 65°C 24 sata da se dobije 0.4 g ondansetron hidroklorid forme H. Ondansetron base (5 g) (17.0 x 10-3 mol) was suspended in 250 ml of absolute ethanol, EtOH. Then an ethanolic solution of HCl (1.5 eq) was added. The reaction mixture was heated (45°C) until a clear solution was obtained and hot filtration of the clear solution was performed. To this filtrate was added tert-butyl methyl ether (200 ml) to precipitate the solid. Then the precipitate was vacuum filtered and dried in an oven at 65°C for 24 hours to obtain 0.4 g of ondansetron hydrochloride form H.
KF=1.7%. KF=1.7%.
Preparacija ondansetron hidroklorid forme I Preparation of ondansetron hydrochloride form I
Primjer 39: Example 39:
Ondansetron hidroklorid forma I je preparirana obrađivanjem hidratiziranog ili bezvodnog ondansetron hidroklorida u parama metanola tri tjedna pri sobnoj temperaturi. Postupak je bio kako slijedi: Uzorak ondansetron hidroklorid forme I mase 100 - 200 mg ili bezvodnog ondansetron hidroklorida držan je u otvorenoj staklenoj boci volumena 10 ml. Otvorena boca je smještena u veći bocu koja je sadržavala nekoliko mililitara metanola. Veća boca je zataljena kako bi se stvorila zasićena atmosfera. Nakon dva tjedna nastala krutina je analizirana rendgenskomdifrakcijom bez dalje obrade i nađeno je da je to ondansetron hidroklorid forma I. Ondansetron hydrochloride Form I was prepared by treating hydrated or anhydrous ondansetron hydrochloride in methanol vapors for three weeks at room temperature. The procedure was as follows: A sample of ondansetron hydrochloride form I weighing 100 - 200 mg or anhydrous ondansetron hydrochloride was kept in an open glass bottle with a volume of 10 ml. The opened bottle was placed in a larger bottle containing several milliliters of methanol. The larger bottle is concealed to create a saturated atmosphere. After two weeks, the resulting solid was analyzed by X-ray diffraction without further processing and found to be ondansetron hydrochloride form I.
Preparacija bezvodne ondansetron forme B iz ondansetron baze Preparation of anhydrous ondansetron form B from ondansetron base
Primjer 40: Example 40:
Ondansetron baza (10 g, 34.1 mmol/ 1 ekv.), 250 ml apsolutnog etanola i 8.4 ml 23.3% HCl u etanolu (51.2 mmol, 1.5 ekv.) dodani su u okruglu tikvicu od 500 ml opremljenu klorkalcijevom cjevčicom i mehaničkom miješalicom. Smjesa je miješana pri sobnoj temperaturi 66 sati. Krutina je onda filtrirana, isprana apsolutnim etanolom (2 x 20 ml) i sušena na 65°C 20 sati da se dobije 8.7g (77%) ondansetron hidroklorid forme B. Ondansetron base (10 g, 34.1 mmol/1 eq.), 250 ml absolute ethanol, and 8.4 ml 23.3% HCl in ethanol (51.2 mmol, 1.5 eq.) were added to a 500 ml round-bottomed flask equipped with a chlorcalcium tube and a mechanical stirrer. The mixture was stirred at room temperature for 66 hours. The solid was then filtered, washed with absolute ethanol (2 x 20 ml) and dried at 65°C for 20 hours to give 8.7g (77%) of ondansetron hydrochloride form B.
KF = 0.66%. KF = 0.66%.
Primjer 41: Example 41:
Ondansetron baza (10 g. 34.1 mmol, l ekv.), 250 ml apsolutnog etanola i 8.4 ml o 23.3% HCl u etanolu (51.2 mmol, 1.5 ekv.) dodani su u okruglu tikvicu od 500 ml opremljenu klorkalcijevom cjevčicom, mehaničkom miješalicom i hladilom. Smjesa je zagrijavana uz refluks da se dobije bistra otopina oko 30 min. Reakcijska smjesa je onda ohlađena do sobne temperature kroz koje vrijeme je nastao talog. Reakcijska smjesa je miješana dodatnih 45 sati. Krutina je onda filtrirana, isprana apsolutnim etanolom (2 x 20 ml) i sušena na 65°C 20 sati da se dobije 8.5 g (76%) ondansetron hidroklorid forme B. Ondansetron base (10 g, 34.1 mmol, 1 eq.), 250 ml of absolute ethanol, and 8.4 ml of 23.3% HCl in ethanol (51.2 mmol, 1.5 eq.) were added to a 500 ml round-bottomed flask equipped with a chlorcalcium tube, a mechanical stirrer, and cooler. The mixture was heated under reflux to obtain a clear solution for about 30 min. The reaction mixture was then cooled to room temperature, during which time a precipitate formed. The reaction mixture was stirred for an additional 45 hours. The solid was then filtered, washed with absolute ethanol (2 x 20 ml) and dried at 65°C for 20 hours to give 8.5 g (76%) of ondansetron hydrochloride form B.
KF = 0.34%. KF = 0.34%.
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| PCT/US2001/048720 WO2002036558A2 (en) | 2000-10-30 | 2001-10-30 | Novel crystal and solvate forms of ondansetron hydrochloride and processes for their preparation |
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| CZ (1) | CZ20031397A3 (en) |
| DE (1) | DE01991193T1 (en) |
| ES (1) | ES2204358T1 (en) |
| HR (1) | HRP20030432A2 (en) |
| HU (1) | HUP0401239A2 (en) |
| IL (1) | IL155644A0 (en) |
| IS (1) | IS6797A (en) |
| MX (1) | MXPA03003761A (en) |
| NO (1) | NO20031928L (en) |
| PL (1) | PL366150A1 (en) |
| SK (1) | SK6182003A3 (en) |
| WO (1) | WO2002036558A2 (en) |
| YU (1) | YU32003A (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20030068583A (en) * | 2001-01-11 | 2003-08-21 | 테바 파마슈티컬 인더스트리즈 리미티드 | An improved process for preparing pure ondansetron hydrochloride dihydrate |
| JP2005529142A (en) | 2002-04-29 | 2005-09-29 | テバ ジョジセルジャール レースベニュタールシャシャーグ | Process for producing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one |
| FI6164U1 (en) * | 2003-01-09 | 2004-03-15 | Synthon Bv | Ondansetronformer |
| US7547791B2 (en) * | 2004-10-26 | 2009-06-16 | Ipca Laboratories Ltd. | One-pot process for the preparation of antiemetic agent, 1,2,3,9-tetrahydro-9-methyl-3[(2-methyl)-1H-imidazole-1-yl)methyl]-4H-carbazol-4-O |
| KR101413613B1 (en) * | 2006-01-27 | 2014-07-10 | 앱탈리스 파마테크, 인코포레이티드 | Drug delivery systems comprising weakly basic selective serotonin 5-HT3 blocking agent and organic acids |
| EP1976492B8 (en) * | 2006-01-27 | 2018-07-04 | Adare Pharmaceuticals, Inc. | Drug delivery systems comprising weakly basic drugs and organic acids |
| JP2010512333A (en) * | 2006-12-07 | 2010-04-22 | ヘルシン ヘルスケア ソシエテ アノニム | Crystalline and amorphous forms of palonosetron hydrochloride. |
| US8133506B2 (en) | 2008-03-12 | 2012-03-13 | Aptalis Pharmatech, Inc. | Drug delivery systems comprising weakly basic drugs and organic acids |
| CN102190595A (en) * | 2010-03-17 | 2011-09-21 | 上海医药工业研究院 | Agomelatine hydrogen bromide hydrate and preparation method thereof |
| CN102190594A (en) * | 2010-03-17 | 2011-09-21 | 上海医药工业研究院 | Agomelatine hydrogen chloride hydrate and preparation method thereof |
| TWI788702B (en) | 2013-11-15 | 2023-01-01 | 美商阿克比治療有限公司 | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4695578A (en) * | 1984-01-25 | 1987-09-22 | Glaxo Group Limited | 1,2,3,9-tetrahydro-3-imidazol-1-ylmethyl-4H-carbazol-4-ones, composition containing them, and method of using them to treat neuronal 5HT function disturbances |
| DE3688296T2 (en) * | 1985-03-14 | 1993-11-04 | Beecham Group Plc | MEDICINES FOR TREATING EMERGENCY. |
| GB8518741D0 (en) * | 1985-07-24 | 1985-08-29 | Glaxo Group Ltd | Process |
| GB8518742D0 (en) * | 1985-07-24 | 1985-08-29 | Glaxo Group Ltd | Process |
| GB8630071D0 (en) * | 1986-12-17 | 1987-01-28 | Glaxo Group Ltd | Medicaments |
| GB8816187D0 (en) * | 1988-07-07 | 1988-08-10 | Glaxo Group Ltd | Medicaments |
| US5344658A (en) * | 1989-06-28 | 1994-09-06 | Glaxo Group Limited | Process and composition using ondansetron |
| EP1022025A3 (en) * | 1991-06-26 | 2002-06-05 | Sepracor, Inc. | Method and compositions for treating emesis nausea and other disorders using optically pure R(+) ondansetron |
| CA2106642C (en) * | 1992-10-14 | 2005-08-16 | Peter Bod | Carbazolone derivatives and process for preparing the same |
| GB9423511D0 (en) * | 1994-11-22 | 1995-01-11 | Glaxo Wellcome Inc | Compositions |
| GB9423588D0 (en) * | 1994-11-22 | 1995-01-11 | Glaxo Wellcome Inc | Compositions |
| CN1045437C (en) * | 1994-12-29 | 1999-10-06 | 中国科学院上海有机化学研究所 | Anthratancitone and its physiological saline synthesis |
| EP1207160A1 (en) * | 2000-11-20 | 2002-05-22 | Hanmi Pharm. Co., Ltd. | Process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3-((2-methyl-1H-imidazol-1-yl)-methyl)-4H-carbazol-4-one |
| JP2005529142A (en) * | 2002-04-29 | 2005-09-29 | テバ ジョジセルジャール レースベニュタールシャシャーグ | Process for producing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one |
| JP2005529908A (en) * | 2002-04-30 | 2005-10-06 | テバ ジョジセルジャール レースベニュタールシャシャーグ | Novel crystalline form of ondansetron, process for producing the same, pharmaceutical composition containing the novel form, and method of treating nausea using the composition |
-
2001
- 2001-10-30 KR KR10-2003-7005876A patent/KR20030042038A/en not_active Application Discontinuation
- 2001-10-30 EP EP01991193A patent/EP1339707A2/en not_active Withdrawn
- 2001-10-30 DE DE0001339707T patent/DE01991193T1/en active Pending
- 2001-10-30 CZ CZ20031397A patent/CZ20031397A3/en unknown
- 2001-10-30 AU AU2002230935A patent/AU2002230935A1/en not_active Abandoned
- 2001-10-30 JP JP2002539318A patent/JP2004525083A/en active Pending
- 2001-10-30 WO PCT/US2001/048720 patent/WO2002036558A2/en not_active Application Discontinuation
- 2001-10-30 ES ES01991193T patent/ES2204358T1/en active Pending
- 2001-10-30 CN CNA018183859A patent/CN1498216A/en active Pending
- 2001-10-30 US US10/016,752 patent/US20020107275A1/en not_active Abandoned
- 2001-10-30 IL IL15564401A patent/IL155644A0/en unknown
- 2001-10-30 MX MXPA03003761A patent/MXPA03003761A/en unknown
- 2001-10-30 PL PL01366150A patent/PL366150A1/en unknown
- 2001-10-30 CA CA002426026A patent/CA2426026A1/en not_active Abandoned
- 2001-10-30 HU HU0401239A patent/HUP0401239A2/en unknown
- 2001-10-30 SK SK618-2003A patent/SK6182003A3/en not_active Application Discontinuation
- 2001-10-30 YU YU32003A patent/YU32003A/en unknown
-
2003
- 2003-04-29 NO NO20031928A patent/NO20031928L/en not_active Application Discontinuation
- 2003-04-29 IS IS6797A patent/IS6797A/en unknown
- 2003-05-28 HR HR20030432A patent/HRP20030432A2/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| ES2204358T1 (en) | 2004-05-01 |
| US20020107275A1 (en) | 2002-08-08 |
| SK6182003A3 (en) | 2004-03-02 |
| WO2002036558A3 (en) | 2003-02-06 |
| NO20031928L (en) | 2003-06-27 |
| CN1498216A (en) | 2004-05-19 |
| EP1339707A2 (en) | 2003-09-03 |
| DE01991193T1 (en) | 2004-07-08 |
| PL366150A1 (en) | 2005-01-24 |
| WO2002036558A2 (en) | 2002-05-10 |
| CA2426026A1 (en) | 2002-05-10 |
| JP2004525083A (en) | 2004-08-19 |
| IL155644A0 (en) | 2003-11-23 |
| MXPA03003761A (en) | 2003-07-28 |
| HUP0401239A2 (en) | 2004-12-28 |
| CZ20031397A3 (en) | 2003-11-12 |
| YU32003A (en) | 2006-05-25 |
| IS6797A (en) | 2003-04-29 |
| AU2002230935A1 (en) | 2002-05-15 |
| KR20030042038A (en) | 2003-05-27 |
| NO20031928D0 (en) | 2003-04-29 |
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